Compounds and compositions as inhibitors of cannabinoid receptor 1 activity

ABSTRACT

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CB1).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/622,508, filed 26 Oct. 2004 and U.S.Provisional Patent Application No. 60/672,670, filed 18 Apr. 2005. Thefull disclosures of these applications are incorporated herein byreference in their entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides compounds, pharmaceutical compositions comprisingsuch compounds and methods of using such compounds to treat or preventdiseases or disorders associated with the activity of CannabinoidReceptor 1 (CB1).

2. Background

The cannabinoids are psychoactive ingredients of marijuana, principallydelta-9-tetrahydrocannabinol. Two cannabinoid receptors have beencloned, CB1 and CB2. CB1 is predominantly expressed in the centralnervous system whereas CB2 is expressed in peripheral tissues,principally in the immune system. Both receptors are members of theG-protein coupled class and their inhibition is linked to adenylatecyclase activity.

The novel compounds of this invention inhibit the activity of CB1 andare, therefore, expected to be useful in the treatment of CB1-associateddiseases or disorders such as, but not limited to, psychosis, memorydeficit, cognitive disorders, migraine, neuropathy, neuroinflammatorydisorders, cerebral vascular accidents, head trauma, anxiety disorders,substance abuse (such as smoking cessation), stress, epilepsy,Parkinson's disease, schizophrenia, osteoporosis, constipation, chronicintestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity,and other eating disorders associated with excessive food intake.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compound selected fromFormula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik:

in which:

Y is selected from O, NR₇ and S; wherein R₇ is selected from hydrogen,hydroxy and C₁₋₆ alkyl;

R₁ is selected from C₅₋₁₀heteroaryl, C₃₋₁₂cyclolalkyl, phenyl andbenzyl; wherein said heteroaryl, cycloalkyl, phenyl and benzyl of R₁ isoptionally substituted with 1 to 3 radicals independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, halo-substituted C₁₋₆ alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈and R₁₀;

R₂ is selected from C₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl andphenoxy; wherein said heterocycloalkyl, heteroaryl, phenyl or phenoxy ofR₂ is optionally substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy,halo-substituted C₁₋₆ alkyl, C₁₋₆ alkenyl, halo-substituted C₁₋₆ alkoxy,—XNR₈R₉, —XOR₈, —XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀,—XNR₈XR₁₀ and —XR₁₀; wherein each X is independently selected from abond, C₁₋₄alkylene and C₂₋₄alkenylene;

R₃ is selected from hydrogen, halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted-C₁₋₆ alkyl,halo-substituted C₁₋₆ alkoxy, —XNR₈R₉, —XR₁₀, —XS(O)₀₋₂R₉, —XC(O)R₁₀,—XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈;

R₄ is selected from C₁₋₆ alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈;

R₅ is selected from hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆ alkoxy,hydroxy-substituted-C₁₋₆ alkyl, hydroxy-substituted-C₁₋₆ alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁ alkylene and C₂₋₄alkenylene;

R₆ is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆ alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈;

R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyl andC₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to which bothare attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀ isselected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl andphenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof; with the proviso that compounds of Formula Ia do not includecompounds of Formula II (as detailed infra).

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof; or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which modulation of CB1 activity can prevent,inhibit or ameliorate the pathology and/or symptomology of the diseases,which method comprises administering to the animal a therapeuticallyeffective amount of a compound of Formula I or a N-oxide derivative,individual isomers and mixture of isomers thereof, or a pharmaceuticallyacceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which CB1 activity contributes to the pathology and/orsymptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₆alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl can be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group. “Heteroaryl” is as defined for aryl whereone or more of the ring members are a heteroatom. For example heteroarylincludes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl,benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole,imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl,1H-pyridin-2-onyl, 6-oxo-1,6-dihydro-pyridin-3-yl, etc.“C₆₋₁₀arylC₀₋₄alkyl” means an aryl as described above connected via aalkylene grouping. For example, C₆₋₁₀arylC₀₋₄alkyl includes phenethyl,benzyl, etc. Heteroaryl also includes the N-oxide derivatives, forexample, pyridine N-oxide derivatives with the following structure:

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-1-yl,2-oxo-piperidin-1-yl, etc.

“Compounds of Formula II” are defined as:5-(4-Isopropyl-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-1-phenyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5,6-di-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5,6-di-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1,5-Diphenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5-o-tolyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Ethoxy-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Isopropyl-phenyl)-1,6-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Methoxy-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Fluoro-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-5-(4-methoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-6-m-tolyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5,6-di-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(4-ethoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Fluoro-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-bromo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1,5-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1,5-Diphenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Methoxy-phenyl)-1,6-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5,6-di-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-1-phenyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(2,4-dimethyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-1-phenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-1-phenyl-5-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Isopropyl-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-1-phenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-ethoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-1-phenyl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3,5-Dimethyl-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Fluoro-phenyl)-1-phenyl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-5-m-tolyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1,6-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-1,6-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1,6-Diphenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Ethoxy-phenyl)-1,6-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(3-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-1-phenyl-5-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(3,5-dimethyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-Phenyl-6-o-tolyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1,5,6-Triphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-5-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Fluoro-phenyl)-1-phenyl-6-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1,6-Diphenyl-5-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Ethoxy-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;and 1,6-Diphenyl-5-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.

“Halogen” (or halo) preferably represents chloro or fluoro, but can alsobe bromo or iodo.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides compounds, compositions and methods forthe treatment of diseases in which inhibition of CB1 activity canprevent, inhibit or ameliorate the pathology and/or symptomology of thediseases, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula I.

In one embodiment, with reference to compounds of the invention, R₁ isselected from phenyl and cyclohexyl; wherein said phenyl and cyclohexylare optionally substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —NR₈R₉,—S(O)₂R₈, —C(O)OR₈ and R₁₀; wherein R₈ and R₉ are independently selectedfrom hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; or R₈ and R₉ together with thenitrogen atom to which both are attached form C₃₋₈heterocycloalkyl orC₅₋₁₀heteroaryl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein said phenyl ofR₁ and heteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈and R₉ and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.

In another embodiment, R₂ is selected from piperazinyl, morpholino,benzthiazolyl, pyridinyl, pyrazolyl, phenyl and phenoxy; wherein saidpiperazinyl, morpholino, benzthiazolyl, pyridinyl, pyrazolyl, phenyl orphenoxy is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈R₁₀ andXR₁₀; wherein each X is independently selected from a bond, C₁₋₄alkyleneand C₂₋₄alkenylene; and R₈ and R₉ are independently selected fromhydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; or R₈ and R₉ together with thenitrogen atom to which both are attached form C₃₋₈heterocycloalkyl orC₅₋₁₀heteroaryl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein saidheteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈ and R₉and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.

In another embodiment, R₄ is selected from C₁₋₆alkyl, phenyl,C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₈heterocycloalkyl-carbonyl andC₃₋₁₂cycloalkyl; wherein any phenyl, cycloalkyl, heteroaryl orheterocycloalkyl of R₄ can optionally be substituted with 1 to 3radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substitutedC₁₋₆alkoxy, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉, —XOR₈, —XC(O)R₁₀ and —XC(O)OR₈; whereineach X is independently selected from a bond, C₁ alkylene andC₂₋₄alkenylene; each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein saidheteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈ and R₉and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.

In another embodiment, R₅ is selected from ethoxy, chloro, hydroxy,dimethyl-amino, morpholino-ethoxy, methoxy, amino, hydroxy-ethoxy,dimethyl-amino-ethoxy, hydroxy-ethyl-amino, morpholino-propoxy andmethyl-piperazinyl-ethoxy.

In another embodiment are compounds Formula Ia:

in which: Y is O; and R₃ is selected from hydrogen, cyano, halo,halo-substituted-C₁₋₆alkyl, cyano-C₁₋₆alkyl, C₁₋₆alkyl, —XS(O)₀₋₂R_(9a),—XC(O)NR_(8a)R_(9a), —XC(O)OR_(8a), —XR₁₀ and —XC(O)R₁₀; wherein eachR_(8a) and R_(9a) are independently selected from hydrogen andC₁₋₆alkyl; or R_(8a) and R_(9a) together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R_(8a) and R_(9a) and additionally the cycloalkyl orphenyl of R₁₀ is optionally substituted with 1 to 3 radicalsindependently selected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆ alkyl,halo-substituted-C₁₋₆ alkoxy, phenyl, —NR_(8a)R_(8a) and —C(O)OR_(8a);wherein each R_(8a) is independently selected from hydrogen andC₁₋₆alkyl.

In a further embodiment, with respect to compounds of Formula Ia, R₁ isselected from phenyl and cyclohexyl; wherein said phenyl and cyclohexylis optionally substituted with 1 to 2 radicals independently selectedfrom chloro, bromo, fluoro, methyl, cyano, methyl-sulfanyl, t-butyl,methoxy-carbonyl, butoxy, trifluoromethoxy, trifluoromethyl, methoxy,isopropyl, piperidinyl and phenyl optionally substituted with halo.

In a further embodiment, R₂ is selected from piperazinyl, morpholino,pyridinyl, pyrazolyl, benzthiazolyl, phenyl and phenoxy; wherein saidpiperazinyl, morpholino, pyridinyl, pyrazolyl, benzthiazolyl, phenyl orphenoxy is optionally substituted with 1 to 2 radicals independentlyselected from: bromo; chloro; fluoro; iodo; hydroxy; isopropyl; methyl;cyclohexyl; oxazolyl; isoxazolyl optionally substituted with 1 to 2methyl radicals; pyrazolidinyl; methyl-carbonyl; amino-carbonyl;morpholino; thienyl; furanyl; cyclohexyl-amino optionally substitutedwith an amino radical; methyl-sulfonyl; trichloromethyl;methoxy-carbonyl; chloro-methyl; butoxy-ethenyl; butoxy-ethyl;trifluoromethyl; trifluoromethoxy; ethoxy-carbonyl; t-butyl;amino-carbonyl; ethyl; propyl; methoxy; methoxy-methyl; carboxy;piperidinyl; piperidinyl-methyl; morpholino-methyl;diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.

In a further embodiment, R₃ is selected from hydrogen, methyl,methyl-sulfonyl, t-butoxy-carbonyl-methyl, amino-carbonyl-methyl,methyl-[1,2,4]oxadiazolyl, cyano-methyl, carboxy, ethoxy-carbonyl,methyl-amino-carbonyl, dimethyl-amino-carbonyl, benzyl, furanyl,pyridinyl, indolyl, morpholino-carbonyl, piperidinyl-amino-carbonyl,piperidinyl-carbonyl, isopropoxy-carbonyl, amino-carbonyl,methyl-sulfanyl, methyl-amino-carbonyl, cyano, methyl-sulfonyl,methyl-piperazinyl, benzyl and phenyl optionally substituted with 1 to 2radicals independently selected from methyl, methoxy, fluoro, chloro,bromo, iodo, cyano, nitro, hydroxy-methyl, ethoxy-carbonyl,methyl-sulfonyl, dimethyl-amino, methyl-amino,cyclopropyl-aminocarbonyl, isopropoxy, trifluoromethyl andtrifluoromethoxy.

In a further embodiment, R₄ is methyl, hydroxy-ethyl, t-butyl, phenyl,benzyl, cyclohexyl, cyclopropyl, pyridinyl, furanyl,morpholino-carbonyl, tetrahydro-thiopyranyl, tetrahydro-thiopyranyl1,1-dioxide and quinolinyl; wherein said phenyl, benzyl, cyclohexyl,cyclopropyl, pyridinyl, furanyl, morpholino-carbonyl,tetrahydro-thiopyranyl, tetrahydro-thiopyranyl 1,1-dioxide andquinolinyl of R₄ is optionally substituted with 1 to 2 radicalsindependently selected from methyl, cyano, carboxy, aminocarbonyl,methoxy, trifluoromethyl, isopropoxy, methyl-sulfanyl, dimethyl-amino,ethoxy-carbonyl, trifluoromethoxy, cyclopropyl-aminocarbonyl,pyridinyl-aminocarbonyl, cyclohexyl-aminocarbonyl,isoxazolyl-aminocarbonyl, dimethylamino-ethyl-aminocarbonyl,methoxy-ethyl-aminocarbonyl, nitro, amino, fluoro, chloro, bromo,hydroxymethyl, methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.

In another embodiment are compounds of Formula Ic:

in which: Y is O; and R₆ is selected from hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, —XNR₈R₉,—XNR₈S(O)₂R₉, —XR₁₀, —XOXNR₈R₉ and —XNR₈NR₈R₉; wherein each X isindependently selected from a bond, C₁₄alkylene and C₂₋₄alkenylene; eachR₈ is independently selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl;and R₁₀ is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl,C₃₋₁₂cycloalkyl and phenyl; wherein said heteroaryl or heterocycloalkylof R₁₀ or the combination of R₈ and R₉ and additionally the cycloalkylor phenyl of R₁₀ is optionally substituted with 1 to 3 radicalsindependently selected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈ and —C(O)OR₈; wherein eachR₈ is independently selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl.

In a further embodiment, with respect to compounds of Formula Ic, R₁ isselected from phenyl and cyclohexyl; wherein said phenyl and cyclohexylis optionally substituted with 1 to 2 radicals independently selectedfrom chloro, bromo, fluoro, methyl, cyano, methyl-sulfanyl, t-butyl,methoxy-carbonyl, butoxy, trifluoromethoxy, trifluoromethyl, methoxy,isopropyl, piperidinyl and phenyl optionally substituted with halo.

In a further embodiment, R₂ is selected from piperazinyl, morpholino,pyridinyl, pyrazolyl, benzthiazolyl, phenyl and phenoxy; wherein saidpiperazinyl, morpholino, pyridinyl, pyrazolyl, benzthiazolyl, phenyl orphenoxy is optionally substituted with 1 to 2 radicals independentlyselected from: bromo; chloro; fluoro; iodo; hydroxy; isopropyl; methyl;cyclohexyl; oxazolyl; isoxazolyl optionally substituted with 1 to 2methyl radicals; pyrazolidinyl; methyl-carbonyl; amino-carbonyl;morpholino; thienyl; furanyl; cyclohexyl-amino optionally substitutedwith an amino radical; methyl-sulfonyl; trichloromethyl;methoxy-carbonyl; chloro-methyl; butoxy-ethenyl; butoxy-ethyl;trifluoromethyl; trifluoromethoxy; ethoxy-carbonyl; t-butyl;amino-carbonyl; ethyl; propyl; methoxy; methoxy-methyl; carboxy;piperidinyl; piperidinyl-methyl; morpholino-methyl;diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.

In a further embodiment, R₄ is methyl, hydroxy-ethyl, t-butyl, phenyl,benzyl, cyclohexyl, cyclopropyl, pyridinyl, furanyl,morpholino-carbonyl, tetrahydro-thiopyranyl, tetrahydro-thiopyranyl1,1-dioxide and quinolinyl; wherein said phenyl, benzyl, cyclohexyl,cyclopropyl, pyridinyl, furanyl, morpholino-carbonyl,tetrahydro-thiopyranyl, tetrahydro-thiopyranyl 1,1-dioxide andquinolinyl of R₄ is optionally substituted with 1 to 2 radicalsindependently selected from methyl, cyano, carboxy, aminocarbonyl,methoxy, trifluoromethyl, isopropoxy, methyl-sulfanyl, dimethyl-amino,ethoxy-carbonyl, trifluoromethoxy, cyclopropyl-aminocarbonyl,pyridinyl-aminocarbonyl, cyclohexyl-aminocarbonyl,isoxazolyl-aminocarbonyl, dimethylamino-ethyl-aminocarbonyl,methoxy-ethyl-aminocarbonyl, nitro, amino, fluoro, chloro, bromo,hydroxymethyl, methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.

In a further embodiment, R₆ is selected frommethyl-sulfonyl-aminomethyl, bromomethyl, methyl-sulfonyl-methyl,ethyl(methyl)amino, dimethylamino, methyl, ethyl, cyano, bromo, chloro,fluoro, morpholino, methyl-piperazinyl, dimethyl-amino-ethoxy,methyl-amino-amino and hydroxyethyl(methyl)amino and methoxy.

In another embodiment, are compounds selected from Formula Ie, Ig andIh:

in which: Y is O; and R₆ is selected from hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, —XNR₈R₉,—XNR₈S(O)₂R₉, —XR₁₀, —XOXNR₈R₉ and —XNR₈NR₈R₉; wherein each X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene;each R₈ is independently selected from hydrogen, C₁₋₆alkyl andC₂₋₆alkenyl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein saidheteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈ and R₉and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.

In a further embodiment, with respect to compounds of Formula Ie, Ig andIh, R₁ is selected from phenyl and cyclohexyl; wherein said phenyl andcyclohexyl is optionally substituted with 1 to 2 radicals independentlyselected from chloro, bromo, fluoro, methyl, cyano, methyl-sulfanyl,t-butyl, methoxy-carbonyl, butoxy, trifluoromethoxy, trifluoromethyl,methoxy, isopropyl, piperidinyl and phenyl optionally substituted withhalo.

In a further embodiment, R₂ is selected from piperazinyl, morpholino,pyridinyl, pyrazolyl, benzthiazolyl, phenyl and phenoxy; wherein saidpiperazinyl, morpholino, pyridinyl, pyrazolyl, benzthiazolyl, phenyl orphenoxy is optionally substituted with 1 to 2 radicals independentlyselected from: bromo; chloro; fluoro; iodo; hydroxy; isopropyl; methyl;cyclohexyl; oxazolyl; isoxazolyl optionally substituted with 1 to 2methyl radicals; pyrazolidinyl; methyl-carbonyl; amino-carbonyl;morpholino; thienyl; furanyl; cyclohexyl-amino optionally substitutedwith an amino radical; methyl-sulfonyl; trichloromethyl;methoxy-carbonyl; chloro-methyl; butoxy-ethenyl; butoxy-ethyl;trifluoromethyl; trifluoromethoxy; ethoxy-carbonyl; t-butyl;amino-carbonyl; ethyl; propyl; methoxy; methoxy-methyl; carboxy;piperidinyl; piperidinyl-methyl; morpholino-methyl;diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.

In a further embodiment, R₃ is selected from hydrogen, methyl,methyl-sulfonyl, t-butoxy-carbonyl-methyl, amino-carbonyl-methyl,methyl-[1,2,4]oxadiazolyl, cyano-methyl, carboxy, ethoxy-carbonyl,methyl-amino-carbonyl, dimethyl-amino-carbonyl, benzyl, furanyl,pyridinyl, indolyl, morpholino-carbonyl, piperidinyl-amino-carbonyl,piperidinyl-carbonyl, isopropoxy-carbonyl, amino-carbonyl,methyl-sulfanyl, methyl-amino-carbonyl, cyano, methyl-sulfonyl,methyl-piperazinyl, benzyl and phenyl optionally substituted with 1 to 2radicals independently selected from methyl, methoxy, fluoro, chloro,bromo, iodo, cyano, nitro, hydroxy-methyl, ethoxy-carbonyl,methyl-sulfonyl, dimethyl-amino, methyl-amino,cyclopropyl-aminocarbonyl, isopropoxy, trifluoromethyl andtrifluoromethoxy.

In a further embodiment, R₄ is methyl, hydroxy-ethyl, t-butyl, phenyl,benzyl, cyclohexyl, cyclopropyl, pyridinyl, furanyl,morpholino-carbonyl, tetrahydro-thiopyranyl, tetrahydro-thiopyranyl1,1-dioxide and quinolinyl; wherein said phenyl, benzyl, cyclohexyl,cyclopropyl, pyridinyl, furanyl, morpholino-carbonyl,tetrahydro-thiopyranyl, tetrahydro-thiopyranyl 1,1-dioxide andquinolinyl of R₄ is optionally substituted with 1 to 2 radicalsindependently selected from methyl, cyano, carboxy, aminocarbonyl,methoxy, trifluoromethyl, isopropoxy, methyl-sulfanyl, dimethyl-amino,ethoxy-carbonyl, trifluoromethoxy, cyclopropyl-aminocarbonyl,pyridinyl-aminocarbonyl, cyclohexyl-aminocarbonyl,isoxazolyl-aminocarbonyl, dimethylamino-ethyl-aminocarbonyl,methoxy-ethyl-aminocarbonyl, nitro, amino, fluoro, chloro, bromo,hydroxymethyl, methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.

In a further embodiment, R₆ is selected frommethyl-sulfonyl-aminomethyl, bromomethyl, methyl-sulfonyl-methyl,ethyl(methyl)amino, dimethylamino, methyl, ethyl, cyano, bromo, chloro,fluoro, morpholino, methyl-piperazinyl, dimethyl-amino-ethoxy,methyl-amino-amino and hydroxyethyl(methyl)amino and methoxy.

Preferred compounds of the invention are selected from5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-quinolin-2-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-pyridin-2-yl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(2-hydroxy-ethyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(2,4-Dichloro-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(2,4-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-bromo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,4-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-biphenyl-4-yl-5-(4-bromo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-1,5-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-pyridin-2-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-cyclohexyl-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-tert-butyl-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Bromo-phenyl)-1-(3-fluoro-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-methoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(4-trifluoromethoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-tert-butyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(2-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,6-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,6-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(2,4,6-trifluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-methoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-biphenyl-4-yl-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[6-(2-Fluoro-phenyl)-4-oxo-1-phenyl-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl]-benzonitrile;6-(2-Fluoro-phenyl)-5-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-tert-Butyl-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[6-(2-Fluoro-phenyl)-4-oxo-1-phenyl-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl]-benzoicacid methyl ester;5-(4-Butoxy-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Biphenyl-4-yl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-trifluoromethoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Benzyl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Cyclohexyl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-Chloro-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol;5,6-Bis-(4-chloro-phenyl)-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;6-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-phenyl-3H-imidazo[4,5-b]pyridin-7-ylamine;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(morpholine-4-carbonyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine;2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethanol;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;[5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine;5-(4-Bromo-phenyl)-1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isoxazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzamide;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrimidin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-methyl-pyrimidin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;5-(4-chloro-phenyl)-6-(3′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(4-imidazol-1-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-phenyl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-benzothiazol-2-yl-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-p-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;1-(4-Chloro-phenyl)-2-(4-isopropyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;5-(4-Bromo-phenyl)-1-phenyl-6-pyridin-3-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-pyridin-3-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-piperidin-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4′-trifluoromethyl-biphenyl-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-thiophen-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;{2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethyl}-dimethyl-amine;2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-ethanol;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(3-morpholin-4-yl-propoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-2-yl-phenyl)-1,9-dihydro-purin-6-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-piperidin-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-phenoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-phenyl-6-(4-phenyl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-2-fluoro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-2-chloro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2-fluoro-4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Chloro-4-morpholin-4-yl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(3-Chloro-biphenyl-4-yl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-furan-3-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-Biphenyl-4-yl-5-(4-chloro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[1-(3-fluoro-phenyl)-1H-pyrazol-4-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid methyl ester;5-(4-Bromo-phenyl)-6-morpholin-4-yl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(4-isopropyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazol-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-amino-cyclohexylamino)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-3-fluoro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid ethyl ester;5-(4-Chloro-phenyl)-6-(2-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3-fluoro-4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[3-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[2-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[2-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[2-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[2-Chloro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-o-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-m-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;7-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;9-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-cyclopropyl-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzonitrile;1-(4-Chloro-phenyl)-9-phenyl-2-(4-thiophen-3-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-4-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-Biphenyl-4-yl-2-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1,2-Bis-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Bromo-phenyl)-9-phenyl-2-(2-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-m-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-o-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,3-difluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-fluoro-3-methyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-nitro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-furan-3-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3,5-difluoro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-isopropoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-trifluoromethoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3,5-dimethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3,5-dimethyl-phenyl)-1,9-dihydro-purin-6-one;2-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-nitro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-furan-3-yl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3,5-difluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(2-fluoro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(5-fluoro-2-methoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-tert-butyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(3′,5′-difluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(3′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-pyridin-3-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-pyridin-3-yl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-pyridin-4-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-fluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-fluoro-phenyl)-1,9-dihydro-purin-6-one;2-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-indole-1-carboxylicacid tert-butyl ester;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-hydroxymethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-hydroxymethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-difluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-difluoro-phenyl)-1,9-dihydro-purin-6-one;7-(5-Chloro-2-methyl-phenyl)-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;9-(5-Chloro-2-methyl-phenyl)-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-dichloro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-nitro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-nitro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzoicacid ethyl ester;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-N-cyclopropyl-benzamide;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclopropyl-benzamide;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-2-methyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(5-fluoro-2-methyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-methoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-methoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-methanesulfonyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-methanesulfonyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-dimethylamino-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-dimethylamino-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-7-(2-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-dimethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-dimethyl-phenyl)-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzoicacid ethyl ester;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-methylamino-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3-fluoro-4-trifluoromethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-(2-methoxy-5-methyl-phenyl)-2-p-tolyl-1,9-dihydro-purin-6-one;3-[1-(4-Bromo-phenyl)-6-oxo-2-p-tolyl-1,6-dihydro-purin-9-yl]-benzonitrile;3-[1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2-fluoro-4-methyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2-fluoro-4-trifluoromethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dimethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-2-fluoro-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid methyl ester;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-isobutyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-3-yl-phenyl)-1,9-dihydro-purin-6-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5,6-bis-(4-chloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-(4-methyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoicacid;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-hydroxymethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(morpholine-4-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(piperidine-1-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Chloro-phenyl)-8-(ethyl-methyl-amino)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-8-dimethylamino-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-6-oxo-9-phenyl-2-(4-trifluoromethyl-phenyl)-6,9-dihydro-1H-purine-8-carbonitrile;8-Bromo-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(ethyl-methyl-amino)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-morpholin-4-yl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(4-methyl-piperazin-1-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(2-dimethylamino-ethoxy)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(N′-methyl-hydrazino)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-methoxy-9-phenyl-1,9-dihydro-purin-6-one;8-Bromo-2-(4-bromo-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-4-yl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-biphenyl-4-yl-6-(4-chloro-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-bromo-phenyl)-1-methyl-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-1-methanesulfonyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylicacid dimethylamide;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-2-methyl-3-phenyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-1-methyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-2-yl]-aceticacid tert-butyl ester;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-aceticacid tert-butyl ester;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-1-methanesulfonyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,3-d]pyrimidin-7-one;5-(4-chloro-phenyl)-6-[4-(2-methyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(4-methyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-biphenyl-4-yl-6-(4-chloro-phenyl)-3-phenyl-6H-isoxazolo[4,3-d]pyrimidin-7-one;2-[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetamide;5-(4-chloro-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-6-(4-pyridin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetonitrile;(1-{4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-1H-imidazol-4-yl)-acetonitrile;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2-ethyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2,4-dimethyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-1-methyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one;6-(4-chloro-phenyl)-1-methyl-3-phenyl-5-(4-pyridin-2-yl-phenyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-2-methyl-3-phenyl-5-(4-pyridin-2-yl-phenyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(1H-imidazol-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-6-(4-pyridin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(3-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-3-methanesulfonyl-6-[4-(1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(4-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(6-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid dimethylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-3-(morpholine-4-carbonyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid piperidin-1-ylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-3-(piperidine-1-carbonyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid isopropyl ester;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid tert-butyl ester;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;6-[4-(2-Butoxy-vinyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Butoxy-ethyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(1-methyl-1-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-methyl-2H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrimidin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(6-Amino-pyrazin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;3-{4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-pyrazine-2-carbonitrile;5-(4-Chloro-phenyl)-6-[4-(3,6-dimethyl-pyrazin-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isoxazol-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(1-methyl-1H-imidazol-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Isopropyl-phenyl)-1-phenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Isopropyl-phenyl)-1-phenyl-5-(3-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-3-methyl-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3,5-Difluoro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3,4-Dichloro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;5-(3-Fluoro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Bromo-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamide;N-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-methanesulfonamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-methanesulfonylmethyl-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclopropyl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-pyridin-3-yl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclohexyl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-(2-dimethylamino-ethyl)-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-(2-methoxy-ethyl)-benzamide;1-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid;2-(4-Bromo-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyrazol-1-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-imidazol-1-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2,9-diphenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-[1,2,4]oxadiazol-5-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-hydroxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloromethyl-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-piperidin-1-ylmethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-morpholin-4-ylmethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-diethylaminomethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(isobutylamino-methyl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-{4-[(cyclopropylmethyl-amino)-methyl]-phenyl}-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-isopropoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-vinyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-cyclopropyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Butoxy-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-methyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-cyclohexyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-oxazol-5-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-7-phenyl-1-p-tolyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4-isopropyl-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;8-Bromo-1-(4-bromo-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-methoxy-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-6-oxo-9-phenyl-2-p-tolyl-6,9-dihydro-1H-purine-8-carbonitrile;1-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;7-Benzyl-2-biphenyl-4-yl-1-(4-chloro-phenyl)-1,7-dihydro-purin-6-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;4-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-p-tolyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-cyclopropyl-1,9-dihydro-purin-6-one;7-Benzyl-1-biphenyl-4-yl-2-(4-chloro-phenyl)-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(3′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(1-oxy-pyridin-4-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(2′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trichloromethyl-phenyl)-1,9-dihydro-purin-6-one;4-[1-(4-Bromo-phenyl)-8-ethyl-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid methyl ester;2-[4-(6-Amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;and1-(4-Chloro-phenyl)-2-(4-methanesulfonyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one.

A further embodiment provides for a method of treating a diseasemediated by the Cannabinoid-1 receptor (for example, an eating disorderassociated with excessive food intake like obesity, bulimia nervosa, andcompulsive eating disorders) comprising administration of to a patientin need of such treatment of a therapeutically effective amount of acompound selected from Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ijand Ik:

in which:

Y is selected from O, NR₇ and S; wherein R₇ is selected from hydrogen,hydroxy and C₁₋₆alkyl;

R₁ is selected from C₅₋₁₀heteroaryl, C₃₋₁₂cyclolalkyl, phenyl andbenzyl; wherein said heteroaryl, cycloalkyl, phenyl and benzyl of R₁ isoptionally substituted with 1 to 3 radicals independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —NR₈, R₉, —S(O)₀₋₂R₈, —C(O)OR₈and R₁₀;

R₂ is selected from C₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl andphenoxy; wherein said heterocycloalkyl, heteroaryl, phenyl or phenoxy ofR₂ is optionally substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XOR₈, —XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀,—XNR₈XR₁₀ and —XR₁₀; wherein each X is independently selected from abond, C₁₋₄alkylene and C₂₋₄alkenylene;

R₃ is selected from hydrogen, halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀, —XS(O)₀₋₂R₉, —XC(O)R₁₀,—XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈;

R₄ is selected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈;

R₅ is selected from hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene;

R₆ is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆ alkyl, halo-substituted C₁₋₆ alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈;

R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyl andC₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to which bothare attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀ isselected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl andphenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆ alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆ alkoxy,hydroxy-substituted-C₁₋₆ alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.

Another embodiment provides for a method of preventing obesity in aperson at risk for obesity comprising administration to said person ofabout 0.001 mg to about 100 mg per kg of a compound selected fromFormula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik:

in which:

Y is selected from O, NR₇ and S; wherein R₇ is selected from hydrogen,hydroxy and C₁₋₆alkyl;

R₁ is selected from C₅₋₁₀heteroaryl, C₃₋₁₂cyclolalkyl, phenyl andbenzyl; wherein said heteroaryl, cycloalkyl, phenyl and benzyl of R₁ isoptionally substituted with 1 to 3 radicals independently selected fromhalo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ andR₁₀;

R₂ is selected from C₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl andphenoxy; wherein said heterocycloalkyl, heteroaryl, phenyl or phenoxy ofR₂ is optionally substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XOR₈, —XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀,—XNR₈XR₁₀ and —XR₁₀; wherein each X is independently selected from abond, C₁₋₄alkylene and C₂₋₄alkenylene;

R₃ is selected from hydrogen, halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted C₁₋₆ alkoxy, —XNR₈R₉, —XR₁₀, —XS(O)₀₋₂R₉, —XC(O)R₁₀,—XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈;

R₄ is selected from C₁₋₆ alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆ alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈;

R₅ is selected from hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆ alkyl, halo-substituted-C₁₋₆ alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene;

R₆ is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆ alkyl, halo-substituted C₁₋₆ alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈;

R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyl andC₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to which bothare attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀ isselected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl andphenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆ alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆ alkoxy,hydroxy-substituted-C₁₋₆ alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.

Preferred compounds of Formula I are detailed in the Examples and TableI, infra.

Pharmacology and Utility

Compounds of the invention inhibit the activity of CB1 and, as such, areuseful for treating diseases or disorders in which the activity of CB1contributes to the pathology and/or symptomology of the disease. Thisinvention further provides compounds of this invention for use in thepreparation of medicaments for the treatment of diseases or disorders inwhich CB1 activity contributes to the pathology and/or symptomology ofthe disease. CB1 mediated diseases or conditions include, but are notlimited to, metabolic disorders as well as conditions associated withmetabolic disorders including obesity, bulimia nervosa, compulsiveeating disorders, diabetes, arteriosclerosis, hypertension, polycysticovary disease, cardiovascular disease, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, cholelithiasis and sleep disorders, andhyperlipidemic conditions; or psychiatric disorders such as substanceabuse, psychosis, depression, anxiety, stress, epilepsy, mania andschizophrenia; or cognitive disorders such as dementia includingAlzheimer's disease, memory deficits, short term memory loss andattention deficit disorders; or neurodegenerative disorders such asParkinson's Disease, cerebral apoplexy and craniocerebral trauma,hypotension, catabolism in connection with pulmonary dysfunction andventilator dependency; or cardiac dysfunction including valvulardisease, myocardial infarction, cardiac hypertrophy and congestive heartfailure); or the overall pulmonary dysfunction, transplant rejection,rheumatoid arthritis, migraine, neuropathy, multiple sclerosis,Guillain-Barre syndrome, the inflammatory sequelae of viralencephalitis, cerebral vascular accidents, inflammatory bowel disease,lupus, graft vs. host disease, T-cell mediated hypersensitivity disease,psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome,cancer, contact dermatitis, allergic rhinitis, ischemic or reperfusioninjury, head trauma and movement disorders. The compounds are alsouseful for the treatment of substance abuse disorders, particularly toopiates, alcohol, marijuana, and nicotine including smoking cessation.The compounds are also useful for the treatment of eating disorders byinhibiting excessive food intake and the resulting obesity andcomplications associated therewith, including left ventricularhypertrophy. The compounds are also useful for the treatment ofconstipation and chronic intestinal pseudo-obstruction, as well as forthe treatment of asthma, osteopororsis, and cirrhosis of the liver.

Marijuana and its derivatives have been used for centuries for medicinaland recreational purposes. A major active ingredient in marijuana andhashish has been determined to be Δ9-Tetrahydrocannabinol (Δ9-THC). Thebiological action of Δ9-THC and other members of the cannabinoid familyoccurs through two G-protein coupled receptors termed CB1 and CB2. TheCB1 receptor is primarily found in the central and peripheral nervoussystems and to a lesser extent in several peripheral organs.

The CB2 receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ9-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each beendisrupted in mice. The CB1 receptor knockout mice appeared normal andfertile. They were resistant to the effects of Δ9-THC and demonstrated astrong reduction in the reinforcing properties of morphine and theseverity of withdrawal syndrome. They also demonstrated reduced motoractivity and hypoalgesia. The CB2 receptor knockout mice were alsohealthy and fertile. They were not resistant to the central nervoussystem mediated effects of administered Δ9-THC. There were some effectson immune cell activation, reinforcing the role for the CB2 receptor inimmune system functions.

Excessive exposure to Δ9-THC can lead to overeating, psychosis,hypothermia, memory loss, and sedation.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverseagonists) is supported by the finding that presynaptic cannabinoid CB1receptors mediate the inhibition of noradrenalin release.

Treatment of cirrhosis of the liver with CB1 receptor modulators issupported by the finding that a CB1 receptor modulator will reverse thelow blood pressure observed in rats with carbon tetrachloride-inducedliver cirrhosis and will lower the elevated mesenteric blood flow andportal vein pressure.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrollidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions can be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they can also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations can also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such cancontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other substances used in the treatment of diseases ordisorders, such as, psychosis, memory deficit, cognitive disorders,migraine, neuropathy, neuroinflammatory disorders, cerebral vascularaccidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson'sdisease, schizophrenia, substance abuse disorders such as smokingcessation, osteoporosis, constipation, chronic intestinalpseudo-obstruction, cirrhosis of the liver, asthma, obesity, and othereating disorders associated with excessive food intake, obesity, etc.(see “Pharmacology and Utility”, supra). Where the compounds of theinvention are administered in conjunction with other therapies, dosagesof the co-administered compounds will of course vary depending on thetype of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

A combined preparation or pharmaceutical composition can comprise acompound of the invention as defined above or a pharmaceuticalacceptable salt thereof and at least one active ingredient selectedfrom:

a) anti-diabetic agents such as insulin, insulin derivatives andmimetics; insulin secretagogues such as the sulfonylureas, e.g.,Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptorligands such as meglitinides, e.g., nateglinide and repaglinide; insulinsensitizer such as protein tyrosine phosphatase-1B (PTP-1B) inhibitorssuch as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such asSB-517955, SB-4195052, SB-216763, N,N-57-05441 and N,N-57-05445; RXRligands such as GW-0791 and AGN-194204; sodium-dependent glucoseco-transporter inhibitors such as T-1095; glycogen phosphorylase Ainhibitors such as BAY R3401; biguanides such as metformin;alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon likepeptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; DPPIV(dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237(vildagliptin—Example 1 of WO 00/34241), MK-0431, saxagliptin, GSK23A;an AGE breaker; a thiazolidone derivative (glitazone) such aspioglitazone, rosiglitazone, or(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid described in the patent application WO 03/043985, as compound 19 ofExample 4, a non-glitazone type PPAR gamma agonist e.g. GI-262570;Diacylglycerol acetyltransferase (DGAT) inhibitors such as thosedisclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO2004047755;

b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors, e.g., lovastatin and related compoundssuch as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin,simvastatin and related compounds such as those disclosed in U.S. Pat.Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such asthose disclosed in U.S. Pat. No. 4,346,227, cerivastatin, mevastatin andrelated compounds such as those disclosed in U.S. Pat. No. 3,983,140,velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin andrelated statin compounds disclosed in U.S. Pat. No. 5,753,675,rivastatin, pyrazole analogs of mevalonolactone derivatives as disclosedin U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives asdisclosed in French Patent No. 2,596,393,2,3-disubstituted pyrrole,furan and thiophene derivatives as disclosed in European PatentApplication No. 0221025, naphthyl analogs of mevalonolactone asdisclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such asdisclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin(lovastatin) as disclosed in European Patent Application No. 0,142,146A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos.5,506,219 and 5,691,322. In addition, phosphinic acid compounds usefulin inhibiting HMG CoA reductase suitable for use herein are disclosed inGB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) andLXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acidand aspirin;

c) an anti-obesity agent or appetite regulating agent such asmelanocortin receptor (MC4R) agonists, melanin-concentrating hormonereceptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR)antagonists, galanin receptor modulators, orexin antagonists, CCKagonists, GLP-1 agonists, and other Pre-proglucagon-derived peptides;NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropinreleasing factor agonists, histamine receptor-3 (H3) modulators, aP2inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoAcarboxylase (ACC) inihibitors, II-β-HSD-1 inhibitors, adinopectinreceptor modulators; beta 3 adrenergic agonists, such as AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator,such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CalSF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-1 inhibitoras disclosed in WO2005011655, a lipase inhibitor, such as orlistat orATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT-933(Biovitrum)), monoamine reuptake inhibitors or releasing agents, such asfenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine,sertraline, chlorphentermine, cloforex, clortermine, picilorex,sibutramine, dexamphetamine, phentermine, phenylpropanolamine ormazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF(ciliary neurotrophic factor)/Axokine® (Regeneron), BDNF (brain-derivedneurotrophic factor), leptin and leptin receptor modulators,phentermine, leptin, bromocriptine, dexamphetamine, amphetamine,fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine,mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine,bupropion, topiramate, diethylpropion, benzphetamine,phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine;

d) anti-hypertensive agents such as loop diuretics such as ethacrynicacid, furosemide and torsemide; diuretics such as thiazide derivatives,chlorithiazide, hydrochlorothiazide, amiloride; angiotensin convertingenzyme (ACE) inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan,terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEPinhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensinII antagonists such as candesartan, eprosartan, irbesartan, losartan,telmisartan and valsartan, in particular valsartan; renin inhibitorssuch as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168;beta-adrenergic receptor blockers such as acebutolol, atenolol,betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol andtimolol; inotropic agents such as digoxin, dobutamine and milrinone;calcium channel blockers such as amlodipine, bepridil, diltiazem,felodipine, nicardipine, nimodipine, nifedipine, nisoldipine andverapamil; aldosterone receptor antagonists; aldosterone synthaseinhibitors; and dual ET/AII antagonist such as those disclosed in WO00/01389.

e) a HDL increasing compound;

f) Cholesterol absorption modulator such as Zetia® and KT6-971;

g) Apo-A1 analogues and mimetics;

h) thrombin inhibitors such as Ximelagatran;

i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone;

j) Inhibitors of platelet aggregation such as aspirin, clopidogrelbisulfate;

k) estrogen, testosterone, a selective estrogen receptor modulator, aselective androgen receptor modulator;

l) a chemotherapeutic agent such as aromatase inhibitors e.g. femara,anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors,microtubule active agents, alkylating agents, antineoplasticantimetabolites, platin compounds, compounds decreasing the proteinkinase activity such as a PDGF receptor tyrosine kinase inhibitorpreferably Imatinib({N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine})described in the European patent application EP-A-0 564 409 as example21 or4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidedescribed in the patent application WO 04/005281 as example 92; and

m) an agent interacting with a 5-HT₃ receptor and/or an agentinteracting with 5-HT₄ receptor such as tegaserod described in the U.S.Pat. No. 5,510,353 as example 13, tegaserod hydrogen maleate, cisapride,cilansetron;

n) an agent for treating tobacco abuse, e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban®)and nicotine replacement therapies;

o) an agent for treating erectile dysfunction, e.g., dopaminergicagents, such as apomorphine), ADD/ADHD agents (e.g., Ritalin®,Strattera®, Concerta® and Adderall®);

p) an agent for treating alcoholism, such as opioid antagonists (e.g.,naltrexone (also known under the tradename ReVia®) and nalmefene),disulfuram (also known under the tradename Antabuse®), and acamprosate(also known under the tradename Campral®)). In addition, agents forreducing alcohol withdrawal symptoms may also be co-administered, suchas benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin®);

q) other agents that are useful including anti-inflammatory agents(e.g., COX-2 inhibitors); antidepressants (e.g., fluoxetinehydrochloride (Prozac®)); cognitive improvement agents (e.g., donepezilhydrochloride (Aircept®) and other acetylcholinesterase inhibitors);neuroprotective agents (e.g., memantine); antipsychotic medications(e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine(Zyprexa®));

or, in each case a pharmaceutically acceptable salt thereof; andoptionally a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

In the following schemes, several methods of preparing the compounds ofthe present invention are illustrative. One of skill in the art willappreciate that these methods are representative, and in no wayinclusive of all methods for preparing the compounds of the presentinvention. The radicals in the schemes are as described in Formula I.

An illustration of the synthesis of the compounds in the presentinvention of Formula Ib, in which R₁ and R₂ are selected from optionallysubstituted phenyl (e.g. Ar¹ and Ar²), is given in Scheme 1.1,2-diarylethanone 1-a can be synthesized using methods reported by M.Wilsterman et al. WO 03051850 and G. M. Anstead, et al., J. Med. Chem.,1990, 33, 2726. Diarylethanone 1-a is heated with5-amino-pyrazole-4-carbonitrile in dichloromethane in the presence ofTiCl₄ at high temperature (100° C. to 160° C., preferably 160° C.) toprovide the pyrazolo[3,4-b]pyridin-4-ylamine 1-b. The 4-amino group ofcompound 1-b is converted to R₅ (R₅ can be halo, alkoxy and etc.) bytransformations such as diazotization with tert-butyl nitrite or sodiumnitrite under acidic condition followed by treatment with appropriatenucleophiles to provide 1-c.

5-amino-pyrazole-4-carbonitriles used in this invention are prepared asdescribed in (a) Peat, A. J. et al Bioorg. & Med. Chem. Lett. (2004),14(9), 2127-2130; (b) Meegalla, S. K. et al Bioorg. & Med. Chem. Lett.(2003), 13(22), 4035-4037; (c) Dooley, M. J. et al Australian J. Chem.(1989), 42(5), 747-50; (d) Reid, W. et al Tetrahedron (1988), 44(23),7155-62.

An illustration of the synthesis of the compounds in the presentinvention of Formula Ia is given in Reaction Scheme 2. An amine 2-a isreacted with an acid chloride 2-b (or its corresponding carboxylic acid)under standard amide formation conditions to provide 2-c. The amide 2-cis treated with chlorination reagents, such as thionyl chloride, oxalylchloride, oxyphosphorus trichloride and etc., to provide 2-d. Theimidoyl chloride 2-d is condensed with 5-amino-4-pyrazole-carboxylate2-e (R^(a) is methyl or ethyl) upon heating in the presence of a strongLewis acid (e.g. TiCl₄) to provide an amidine intermediate, which iscyclized in situ to 1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one 2-f.Amide coupling reactions were carried out under standard conditions,such as those described in (1) M. Bodanszky et al “The Practice ofPeptide Synthesis”, Springer-Verlay 2^(nd) ed. 1994; (2) A. R.Chamberlin, Chem. Rev. 1997, 97, 2243-66.

5-amino-4-pyrazole-carboxylates 2-e used in this invention aresynthesized as described in (a) Abass, M. Phosphorus, Sulfur and Siliconand the Related Elements (2003), 178(7), 1413-1432; (b) Beck, James R.et al J. Heterocyclic Chem. (1987), 24(3), 693-5; (c) Sunder, S. et alJ. Heterocyclic Chem. (1980), 17(7), 1527-9; (d) Beck, James R. et al J.Heterocyclic Chem. (1988), 25(3), 955-8; (e) Ryckmans, T. et alTetrahedron (1997), 53(5), 1729-1734; (f) Organ, Michael G. et al J.Combi. Chem. (2003), 5(2), 118-124; (g) Kopp, M. et al J. HeterocyclicChem. (2001), 38(5), 1045-1050.

An illustration of the synthesis of the compounds in the presentinvention of Formula Ic is given in Reaction Scheme 3. Ethylcyanoglycoxylate-2-oxime 3-a is reduced according to literatureprecedent (De Meester et al Heterocycl. Chem. 1987, 24, 441) to2-cyanglycine ethyl ester 3-b Amine 3-b is then condensed with triethylorthoformate. Without purification, the resultingcyano[(1-ethoxymethylene)amino]acetate 3-c is treated directly withamine R₄NH₂ to provide 5-amino-1H-imidazole-4-carboxylate 3-d. Synthesesof compound 3-d are also described in (a) Collins M. et al Inorg. Chem.Commun. 2000, 3, 453; (b) Herr, R. et al J. Org. Chem. 2002, 67(1),188-193; (c) Suwinski, J. et al Eur. J. Org. Chem. 2003, (6), 1080-1084.5-Amino-1H-imidazole-4-carboxylate 3-d is converted to1,9-dihydro-purin-6-one 3-e by the procedures described in Scheme 2.

Compounds in the present invention of Formula Ia can also be made by theprocedures given in Reaction Scheme 4. 5-Amino-pyrazole-4-carboxylate2-e reacts with acid chloride R₂(C═O)Cl giving the N,N-diacylatedintermediate 4-b which is then treated with an excess amount of lithiumamide R₁NHLi to form intermediate 4-c (R^(a) is methyl or ethyl). Ringclosure of 4-c upon treatment with trimethylsilyl chloride andtriethylamine gives 1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one 2-f. Aprocedure similar to the annulation step used here is described byMiyata, K. et al U.S. Pat. No. 5,922,866. Other procedures to effect theconversion of compound 4-c to compound 2-f are described in (a)Brzozowski Z. et al J. Med. Chem. (2002), 45(2), 430-37; (b) Zaher, H.A. et al Indian J. Chem. (1974), 12(11), 1212-15.

Reaction scheme 5 illustrates the preparation of bi-aryl orheteroaryl-phenyl derivatives. Under the standard Suzuki or Stillecoupling conditions, Bromo (or iodo) substituted 1,9-dihydro-purin-6-one5-a is coupled with suitable boronic acids or stannane to form desiredpurinone derivatives 5-b.

Reaction scheme 6 describes the synthesis of the compounds with variousaryl or heteroaryl R⁴ by a modified cupper complex-catalyzed crosscoupling reaction of arylboronic acids with imidazoles developed from J.Collman's laboratory (ref. Org. Lett. 2000, 2, 1233.) The startingmaterial required for this synthesis, ethyl 4-amino-1-benzylimidazolecarboxylate, is readily prepared in a large scale from commerciallyavailable N-benzylglycine ethyl ester (ref. Synthesis 1995, 855).

Detailed descriptions of the synthesis of compounds of the Invention aregiven in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, or the like) in a suitable inert organic solvent(e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) that of reaction scheme 1, 2, 3, 4, 5 or 6; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing intermediates (Reference Examples) and Examples thatillustrate the preparation of compounds of the invention.

Reference I Preparation of 5-Amino-1-cyclohexyl-1H-pyrazole-4-carboxylicacid ethyl ester

To a round bottom flask is added cyclohexyl-hydrazine hydrochloride (4.5g, 30 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (5.1 g, 30 mmol),sodium bicarbonate (2.6 g, 30.9 mmol) and 40 mL of ethanol. The mixtureis heated to 80° C. for 1 hour, cooled down to room temperature andconcentrated. The residue is dissolved in chloroform and washed withwater, dried over sodium sulfate. After removal of the solvent, thesolid is recrystallized from ethyl acetate: ¹HNMR (CDCl₃): δ 7.40 (1H,s), 4.77 (2H, brs), 4.05 (2H, q, J=7.2 Hz), 3.50 (1H, m), 1.61-1.71 (6H,m), 1.50 (1H, m), 1.02-1.21 (3H, m), 1.11 (3H, t, J=7.2 Hz).

Example 15-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one

Step A: Commercially available 5-amino-1-phenyl-1H-pyrazole-4-carboxylicacid ethyl ester (1, 2.31 g, 10 mmol) is added to a flask and 10 mL ofdry pyridine is added. 2,4-Dichloro-benzoyl chloride (4.18 g, 20.0 mmol)is added via syringe to the stirring reaction mixture. The reaction isheated to reflux for 3 hours. The resulting slurry is poured into 500 mLof 1 M HCl and the crude product is extracted out in 2×200 mL of DCM.The organic layer is washed with 100 mL of 1 M HCl, followed by 300 mLsaturated aqueous sodium bicarbonate and brine. The organic layer isdried over MgSO₄, filtered and concentrated. The crude product isrecrystallized from hot hexanes with a minimal amount of dichloromethaneadded to give 2: LC/MS found: 578.1 (M+H⁺).

Step B:

4-Chloro-aniline (663 mg, 5.2 mmol) is added to a three neck flask whichis sealed with septa, equipped with an oil bubbler and purged with drynitrogen. Anhydrous THF (20 mL) is added via syringe under an inertatmosphere. The amine is deprotonated with n-Bu-Li (2.5 M, 2.07 mL, 5.2mmol) at room temperature. The reaction is stirred for 10 minutes and of5-[bis-(2,4-dichloro-benzoyl)-amino]-1-phenyl-1H-pyrazole-4-carboxylicacid ethyl ester (2, 500 mg, 0.866 mmol) is added as a solid under apositive purge of nitrogen. The resulting reaction mixture is stirredfor 30 minutes and quenched by pouring into saturated aqueous ammoniumchloride. The crude product is extracted in 100 mL of ethyl acetate,washed with 1 M HCl, brine, and dried over MgSO₄. The organic layer isfiltered and concentrated to dryness. The dark crude material isrecrystallized from hot DCM yielding yellow crystals of 3: ¹H NMR(DMSO-d6, 400 MHz) δ 10.7 (s, 1H), 10.1 (s, 1H), 8.4 (s, 1H), 7.75 (d,J=8.9 Hz, 2H), 7.73 (s, br, 1H), 7.66-7.53 (m, 6H), 7.5-7.46 (m, 1H),7.41 (d, J=8.9 Hz, 2H). LC/MS found: 485.0 (M+H⁺).

Step C. 5-(2,4-Dichloro-benzoylamino)-1-phenyl-1H-pyrazole-4-carboxylicacid (4-chloro-phenyl)-amide (3, 1.1 g, 2.26 mmol) is placed in a largemicrowave tube with 12 mL of dry TEA and 5 mL of freshly distilledTMSCl. The tube is sealed and the resulting slurry is heated to 100° C.in an oil bath overnight. The reaction mixture is quenched with 500 mLof 1 M HCl and the product is extracted in 2×200 mL of DCM. The organiclayer is washed with 100 mL of HCl, 300 mL of saturated aqueous sodiumbicarbonate, and 300 mL of brine. The organic layer is dried over MgSO₄,filtered and concentrated. The crude material is purified by flashchromatography to yield 1.0 g of 4 as a white solid: ¹H NMR (CDCl₃, 400MHz) δ 8.35 (s, 1H), 8.09 (d, J=7.58 Hz, 2H), 7.51-7.47 (m, 2H), 7.39(d, J=7.5 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.3-7.28 (m, 2H), 7.21-7.16(m, 2H), 7.04-7.0 (m, 1H); LC/MS found: 469.0 (M+1/z).

Example 25-(4-bromo-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of 4-bromoaniline (1, 60.0 mg, 0.35 mmol) indichloromethane (1.5 mL) is added p-toluoyl chloride (2, 46.1 μL, 0.35mmol) and TEA (97.2 μL, 0.70 mmol). The reaction mixture is stirred atroom temperature for 30 minutes to provideN-(4-bromo-phenyl)-4-methyl-benzamide (3). After removal of the solvent,without further purification, 3 is taken by thionyl chloride (0.5 mL)and the mixture is heated at 80° C. for 1 hour before thionyl chlorideis removed in vacuo to provide imidoyl chloride 4. Without furtherpurification, the crude 4 is dissolved in dichloroethane (1.0 mL), andethyl 5-amino-1-phenyl-4-pyrazole-carboxylate (5, 96.8 mg, 0.42 mmol)and TiCl₄ (153.0 μL, 1.40 mmol) are added. The reaction mixture isheated at 160° C. in a microwave for 20 minutes, cooled down, dilutedwith dichloroethane (5 mL), and quenched with H₂O (5 mL). The two layersare separated. The aqueous layer is extracted with dichloroethane. Thecombined dichloroethane layer is washed with brine, dried over MgSO₄,concentrated, and purified by silica gel chromatography followed byreverse phase HPLC to provide5-(4-bromo-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas a white solid product: ¹H NMR (CDCl₃, 400 MHz) δ 8.31 (s, 1H), 8.16(d, 2H), 7.50 (t, 2H), 7.47 (d, 2H), 7.34 (t, 1H), 7.22 (d, 2H), 7.06(d, 2H), 7.02 (d, 2H), 2.32 (s, 3H); HPLC-MS calculated for C₂₄H₁₇BrN₄O(M+H⁺) 457.1, found 457.1.

Example 35-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine

A solution of 2-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-ethanone (300mg, 0.99 mmol) in dichloroethane (3 mL) is stirred at room temperaturewhile TiCl₄ (311 mg, 1.64 mmol) is added dropwise. After the addition,the mixture is stirred at room temperature for 5 minutes and a solutionof 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (150 mg, 0.815 mmol) indichloroethane (3 mL) is added dropwise. After the addition, the mixtureis heated to 125° C. for 5 hours. After cooling, the mixture is pouredinto a mixture of ice cold saturated aqueous NaHCO₃ solution (30 mL) andEtOAc (30 mL). The resultant precipitate is filtered through celite andwashed with EtOAc (2×10 mL). The filtrate is extracted by EtOAc (3×15mL). The organic layers are combined and washed with brine and dried(MgSO₄). After filtering off the drying agent, the filtrate isconcentrated and purified by column chromatography (silica gel, 0%˜40%EtOAc/hexane) to provide the titled compound5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamineas light yellow solid: ¹H NMR (MeOD) δ (ppm) 8.38 (s, 1H), 8.13 (d, 2H),7.48 (t, 2H), 7.34 (d, 1H), 7.27-7.31 (m, 3H), 7.12-7.25 (m, 4H);HPLC-MS calculated for C₂₄H₁₅C₃N₄ (M+H⁺): 465.0, found 465.2.

Examples 4 and 55-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;and5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-ethoxy-1-phenyl-1H-pyrazolo-[3,4-b]pyridine

A solution of5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine(10 mg, 0.022 mol) in EtOH (1 mL) is treated with tert-butyl nitrite (23mg, 0.22 mol) and heated to 80° C. for 16 hours. After cooling down toroom temperature, the mixture is concentrated and purified bypreparative thin layer chromatography to provide5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine(Example 4) and5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridineis also obtained as side product (Example 5). Example 4: ¹H NMR (CDCl₃)δ (ppm) 8.35 (d, 2H), 8.29 (s, 1H), 8.14 (s, 1H), 7.48 (t, 2H), 7.37 (d,1H), 7.28 (t, 1H), 7.23-7.17 (m, 4H), 7.11 (d, 2H); HPLC-MS calculatedfor C₂₄H₁₄C₁₃N₃ (M+H⁺): 450.0, found 450.2. Example 5: ¹H NMR (CDCl₃) δ(ppm) 8.36 (s, 1H), 8.30 (d, 2H), 7.48 (t, 2H), 7.32 (d, 1H), 7.29 (d,1H), 7.18 (d, 2H), 7.05-7.14 (m, 4H), 4.68 (q, 2H), 1.42 (t, 3H);HPLC-MS calculated for C₂₆H₁₈C₁₃N₃O (M+H⁺): 494.1, found 494.2.

Examples 6 and 75-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;and5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(50 mg, 0.104 mmol) is dissolved in 5 mL of acetic anhydride.Concentrated nitric acid (300 μL) is added dropwise over 2 minutes.After the reaction mixture is stirred for 15 minutes, the volatiles arestripped off and the resulting crude material is purified by columnchromatography to give5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneand5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one:¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.8 (d,J=8.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.58-7.52 (m, 1H), 7.33-7.19 (m, 4H),7.16-7.08 (m, 2H), 6.96-6.89 (m, 1H); LC/MS found: 512.0 (M+1/z);

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one:¹H NMR (CDCl₃, 400 MHz) δ 8.42 (d, J=9.1 Hz, 2H), 8.34 (s, 1H), 8.29 (d,J=9.1 Hz, 2H), 7.3-7.11 (m, 6H), 7.01-6.95 (m, 1H); LC/MS found: 512.1(M+1/z).

Example 81-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one

1-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared by dissolving5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-nitro-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(100 mg, 0.194 mmol) in 20 mL of 9:1 dioxane/water. The solution isdegassed and 11 mg of PtO₂ is added under nitrogen. The slurry isdegassed again and placed under balloon pressure hydrogen. The reactionmixture is stirred for 4 hours, degassed, filtered, and concentrated.The crude product is purified by reverse phase HPLC to give the titlecompound: ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (s, 1H), 7.44 (d, J=8.8 Hz,2H), 7.27-7.24 (m, 2H), 7.19-7.17 (m, 3H), 7.13 (dd, J=8.36, 2 Hz, 1H),7.1-7.05 (m, 1H), 6.6 (d, J=8.8 Hz, 2H); LC/MS found: 482.0 (M+1/z).

Example 95-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-quinolin-2-yl-1,5-dihydro-pyrazolo-[3,4-d]pyrimidin-4-one

Step A. synthesis of N-(4-Bromo-phenyl)-2-fluoro-benzamidine.2-fluorobezonitrile (5.00 g, 41.3 mmol) and 4-bromo-aniline (7.20 g,41.8 mmol) are placed in a 150 mL of round bottom flask. To thisstiffing mixture is added AlCl₃ (5.6 g, 41.5 mmol). The mixture isheated to 190° C. for 4 hours and cooled to 50° C. EtOAc (100 mL) isadded and the mixture is neutralized with 20% NaOH solution to pH ˜8.The organic layer is separated and washed with water and brine and driedover sodium sulfate. Removal of the solvent gives the crude product,which is recrystallized from ethyl acetate: ¹HNMR (CDCl₃): δ 7.98 (1H,br), 7.33 (4H, m), 7.15 (1H, t, J=6.8 Hz), 7.04 (1H, dd, J=8.4, 12.0Hz), 6.76 (1H, d, J=8.0 Hz), 5.06 (1H, br).

Step B. synthesis of1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-4-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile.N-(4-bromo-phenyl)-2-fluoro-benzamidine (4.00 g, 13.7 mmol) and2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester (2.50 g, 12.3mmol) are mixed in a reaction tube. The mixture is heated to 130° C. for2.5 hours and cooled to room temperature. Ethyl acetate (50 mL) is addedand the mixture is stirred for 5 minutes. After filtration, pure product(4.1 g) is obtained. The solvent is concentrated, and the residue ispurified on silica gel: ¹HNMR (CDCl₃): δ 7.34 (2H, d, J=8.8 Hz),7.28-732 (1H, m), 7.26 (1H, dt, J=1.6, 6.8 Hz), 7.08 (1H, dt, J=0.8, 6.8Hz), 6.91 (2H, dd, J=1.2, 8.4 Hz), 6.85 (1H, dt, J=0.8, 8.8 Hz), 2.56(3H, s).

Step C. synthesis of3-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-6-methylsulfanyl-5-(quinolin-2-yl-hydrazonomethyl)-3H-pyrimidin-4-one.To a dry round bottom flask is added1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-4-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile(2.0 g, 4.8 mmol). This flask is charged with 15 mL of dichloromethane.The solution is cooled to −20° C. A solution of DIBAL-H (6.5 mL, 1 M indichloromethane) is added slowly over 5 minutes. The resulting solutionis stirred at this temperature for 2 hours and allowed to warm to roomtemperature and stirred for additional 1 hour. The reaction mixture iscooled in an ice bath and quenched with water. The mixture is extractedwith dichloromethane and the extracts are combined, washed with waterand dried over sodium sulfate. After removal of the solvent, the residueis purified on silica gel.

Steps D and E. Synthesis of5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-quinolin-2-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.To a reaction tube is added3-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-6-methylsulfanyl-5-(quinolin-2-yl-hydrazonomethyl)-3H-pyrimidin-4-one(20 mg, 0.05 mmol), quinolin-2-yl-hydrazine (7.5 mg, 0.05 mmol),dichloromethane (1 mL) and catalytic p-toluenesulfonic acid. Thesolution is stirred at room temperature for 1 hour. Solvent is removedand DMF (0.5 mL) is added. The mixture is heated at 130° C. for 6 hoursand purified by preparative LC-MS: ¹HNMR (CDCl₃): δ 8.41 (1H, s), 8.32(1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 7.79(1H, d, J=8.4 Hz), 7.68 (1H, dt, J=1.2, 8.4 Hz), 7.51 (1H, t, J=8.0 Hz),7.66 (2H, d, J=8.8 Hz), 7.25-7.32 (2H, m), 7.08 (1H, dt, J=0.8, 6.8 Hz),6.99 (2H, d, J=6.8 Hz), 6.85 (1H, t, J=9.2 Hz).

Example 684-Chloro-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine

To a solution of5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine(16 mg, 0.034 mmol) in CH₃CN (0.4 mL) is added conc. HCl (0.8 mL). NaNO₂(20 mg, 0.29 mmol) is added into the mixture at 0° C. After theaddition, the mixture is warmed up to room temperature and stirred for24 h. The mixture is then neutralized to pH˜7 by adding saturatedaqueous NaHCO₃ and extracted with EtOAc (3×3 mL). The combined organiclayers are concentrated and purified by preparative thin layerchromatography to provide the titled compound as a white solid (4 mg,24%). ¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.28 (d, 2H), 7.50 (t, 2H),7.27-7.37 (m, 2H), 7.24-7.26 (m, 2H), 7.07-7.16 (m, 4H); HPLC-MScalculated for C₂₄H₁₃Cl₄N₃ (M+1⁺): 484.0, found: 484.1.

Example 695,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol

A solution of 1,2-bis-(4-chloro-phenyl)-ethanone (100 mg, 0.38 mmol) indichloroethane (1 mL) is stirred at room temperature while TiCl₄ (143mg, 0.75 mmol) is added in dropwise. After the addition, the mixture isstirred at room temperature for 5 min and a solution of5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (97 mg, 0.42mmol) in dichloroethane (1 mL) is added dropwise. After the addition,the mixture is heated to 125° C. for 5 h. After cooling down themixture, it is poured into a mixture of ice cold saturated aqueousNaHCO₃ solution (15 mL) and EtOAc (15 mL). The resulted mixture isfiltered through celite to remove the precipitate and washed with EtOAc(2×5 mL). The filtrate is extracted by EtOAc (3×5 mL). The organiclayers are combined and washed with brine and dried (MgSO₄). Afterfiltering off the drying agent, the filtrate is concentrated andpurified by preparative LC/MS to provide the titled compound5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol aslight yellow solid. (55 mg, 31%). ¹H NMR (MeOD) δ (ppm) 8.37 (s, 1H),8.23 (d, 2H), 7.53 (t, 2H), 7.34 (t, 1H), 7.31 (d, 2H), 7.29 (d, 2H),7.23 (d, 2H), 7.15 (d, 2H); HPLC-MS calculated for C₂₄H₁₅C₁₂N₃O (M+1⁺):432.1, found: 432.2.

Example 741-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one

Step A. synthesis of N-(4-Bromo-phenyl)-2,4-dichloro-benzimidoylchloride

To a solution of 4-bromoaniline (0.50 g, 2.9 mmol) and 2,4-dichlorobenzoyl chloride (0.41 mL, 2.9 mmol) in dichloromethane is addedtriethylamine (0.49 mL, 3.49 mmol). After being stirred at roomtemperature for 30 minutes, the solvent is removed and the residue isdissolved in 2 mL of thionyl chloride. The reaction mixture is heated at80° C. for 1 hour and concentrated. The product is used for the nextstep without purification.

Synthesis 5-Amino-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester

A solution of amino-cyano-acetic acid ethyl ester (1.64 g, 12.8 mmol)and triethyl orthoformate (2.13 mL, 12.8 mmol) in acetonitrile is heatedat reflux for 45 minutes. After the reaction mixture is cooled down toroom temperature, aniline (1.17 mL, 12.8 mmol) is added. Solid isprecipitated out after the mixture has been stirred for overnight atroom temperature. Filtration gave a product as a white solid (two stepsyield 59%). ¹H NMR (CDCl₃) δ 7.59 (m, 3H), 7.53 (d, 2H), 7.21 (s, 1H),5.04 (b, 2H), 4.41 (q, 2H), 1.45 (t, 3H); m/z 232.1 (M+1).

Step B. synthesis of1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one

To a solution of N-(4-bromo-phenyl)-2,4-dichloro-benzimidoyl chloride(0.22 mmol) and 5-amino-1-phenyl-1H-imidazole-4-carboxylic acid ethylester (65 mg, 0.27 mmol) in 1,2-dichloroethane is added titaniumtetrachloride (98 μL, 0.89 mmol) dropwise at room temperature. Afteraddition is completed, the reaction mixture is heated at 120° C. for 18hours. After the reaction is quenched with water and the aqueous layeris extracted with ethyl acetate. The organic solvents are combined anddried over magnesium sulfate. Filtration and concentration provide acrude product which is purified by column chromatography gave a whitesolid as product (41 mg, three steps yield 36%). ¹H NMR (CDCl₃) δ (ppm)8.04 (s, 1H), 7.58 (d, 2H), 7.47 (t, 2H), 7.38 (m, 3H), 7.22 (d, 1H),7.15 (b, 1H), 7.07 (m, 2H), 6.91 (b, 1H); HPLC-MS calculated forC₂₃H₁₃BrCl₂N₄O (M+H⁺): 511.0, found 511.0.

Example 771-(4-Bromo-phenyl)-2-(4-methyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one

To a solution of N-(4-bromo-phenyl)-4-methyl-benzimidoyl chloride whichis prepared from 4-bromoaniline (29.2 mg, 0.17 mmol) and 4-methylbenzoyl chloride (22.5 μL, 0.17 mmol), and5-amino-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (50 mg, 0.20mmol) in 1,2-dichloroethane is added titanium tetrachloride (75 μL, 0.68mmol) dropwise at room temperature. After addition, the reaction mixtureis heated at 170° C. for 30 min on microwave reactor. Quenching withwater is followed by extracting with ethyl acetate. The organic solventsare combined and dried over magnesium sulfate. Filtration andconcentration followed by purification with chromatography give a whitesolid as product. ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.12 (s, 1H), 7.70 (d,2H), 7.55 (t, 2H), 7.45 (m, 3H), 7.15 (d, 2H), 7.03 (m, 4H); HPLC-MScalculated for C₂₄H₁₇BrN₄O (M+H⁺): 457.0, found 457.0.

5-amino-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester used aboveis prepared as described below.

A solution of amino-cyano-acetic acid ethyl ester (1.64 g, 12.8 mmol)and triethyl orthoformate (2.13 mL, 12.8 mmol) in acetonitrile washeated at reflux for 45 min. After cooled down to room temperature,aniline (1.17 mL, 12.8 mmol) was added. Stirred at room temperature forovernight, solid precipitated out. Filtration gave a white solid asproduct (two steps yield 59%). ¹H NMR (CDCl₃) δ 7.59 (m, 3H), 7.53 (d,2H), 7.21 (s, 1H), 5.04 (b, 2H), 4.41 (q, 2H), 1.45 (t, 3H); m/z 232.1(M+1).

N-(4-bromo-phenyl)-4-methyl-benzimidoyl chloride used is prepared by thefollowing procedure. To a solution of 4-bromoaniline (29.2 mg, 0.17mmol) and 4-methyl benzoyl chloride (22.5 μL, 0.17 mmol) indichloromethane was added triethylamine (28 μL, 0.20 mmol). Afterstirred at room temperature for 30 minutes, the solvent was removed. Theresidue was added 0.5 mL of thionyl chloride. The reaction mixture washeated at 80° C. for 1 h, concentrated. The product was used in the nextstep reaction.

Example 795-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(morpholine-4-carbonyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

To a solution of5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(208 mg, 0.423 mmol) in aceonitrile (5 mL) is added CAN (1M aqueoussolution, 1.7 mL) at 0° C. After the addition, the mixture is allowed towarm up to room temperature and then heated to 80° C. for 5 h. Aftercooling down to room temperature, the mixture is treated with water (10mL) and extracted with EtOAc (3×10 mL). The organic layers are combinedand washed with water, saturated aqueous NaHCO₃, NaHSO₃ (10% aqueoussolution), brine and dried (MgSO₄). After removing the drying agent byfitration, the solvent is removed under vacuum and the residue ispurified by flash column chromatography (silica gel, 0%˜80% EtOAc/hex)to provide the desired product5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid. (51 mg, 31%). ¹H NMR (CDCl₃, 400 MHz) δ 8.26 (s, 1H),7.41 (d, 2H), 7.29-7.35 (m, 2H), 7.13 (t, 1H), 7.03 (b, 2H), 6.92 (t,1H); HPLC-MS calculated for C₁₇H₁₀BrFN₄O (M+H⁺) 385.0, found 385.0.

Step B:

To a solution of5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(20.0 mg, 0.052 mmol) in anhydrous pyridine (0.5 mL) is added4-morpholinecarbonyl chloride (7.27 μL, 0.062 mmol). The mixture isstirred at room temperature for 2 h before removal of the solvent. Theresidue is purified by preparative LCMS followed by preparative TLC toprovide the title compound (9.1 mg, 35% yield) as a white solid product;¹H NMR (CDCl₃, 400 MHz) δ 8.91 (s, 1H), 7.42-7.28 (m, 4H), 7.11 (t, 1H),7.02 (d, 2H), 6.88 (t, 1H), 4.15-3.84 (m, 8H); HPLC-MS calculated forC₂₂H₁₇BrFN₅O₃ (M+H⁺) 498.0, found 498.0.

Example 80 5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine

Step A:

1,2-Bis-(4-chloro-phenyl)-ethane-1,2-dione is prepared by following theprocedures described in M. Wilsterman et al. WO 03051850. The reactioncrude product is used directly for next step without purification.

Step B:

To a solution of 2-phenyl-2H-pyrazol-3-ylamine (250 mg, 1.57 mmol) inEtOH (3 mL) is added HCl (4N in dioxane, 1.15 mL, 4.6 mmol). The mixtureis then cooled down to −10° C., tert-butyl nitrite (178 mg, 1.73 mmol)is added drop wise. After addition, the mixture is stirred at 0° C. for1 h. The precipitate is collected by filtration to provide4-nitroso-2-phenyl-2H-pyrazol-3-ylamine (180 mg, 60%) as yellow solid.

To a suspension of 4-nitroso-2-phenyl-2H-pyrazol-3-ylamine (100 mg, 0.53mmol) in EtOH (1 mL) is added SnCl₂.2H₂O (240 mg, 1.06 mmol). Themixture is then heated to 60° C. for 30 min After cooling down themixture, it is poured into a mixture of EtOAc (20 mL) and saturatedaqueous NaHCO₃ solution (20 mL). The solid is removed by filtrationthrough Celite. The filtrate is put into separatory funnel to collectthe organic layer, which is washed with brine and dried over MgSO₄.After filtering off the drying agent, the filtrate is concentrated toprovide the crude 2-phenyl-2H-pyrazole-3,4-diamine (−25 mg) and usedimmediately for next step.

Step C:

A mixture of 1,2-bis-(4-chloro-phenyl)-ethane-1,2-dione from Step A (˜20mg), 2-phenyl-2H-pyrazole-3,4-diamine from Step B (25 mg) and p-TSA inMeOH (1 mL) is heated to 80° C. for 2 h. After cooling down to roomtemperature, the mixture is treated with saturated aqueous NaHCO₃solution (3 mL) and extracted with EtOAc (3×2 mL). The organic layersare combined and concentrated. The residue is purified by PreparativeLC/MS to provide the title compound5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine. ¹H NMR(CDCl₃) δ (ppm) 8.51 (s, 1H), 8.34 (d, 2H), 7.56 (t, 2H), 7.46 (d, 2H),7.32˜7.43 (m, 7H); HPLC-MS calculated for C₂₃H₁₄Cl₂N₄ (M+H⁺): 417.1,found: 417.1.

Example 825-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

A mixture of tetrahydro-thiopyran-4-one (226 mg, 2.0 mmol) and hydrazinehydrate (120 mg, 2.4 mmol) in EtOH (3 mL) is stirred at room temperaturefor 2 h when NaBH₄ (148 mg, 4.0 mmol) is added as one portion. Themixture is then stirred at room temperature for 14 h. After quenchingthe reaction by treating with saturated aqueous NH₄Cl solution (1 mL) atroom temperature for 30 min, ethyl(ethoxymethylene)cyano-acetate (677mg, 4.0 mmol) is added as one portion. The mixture is then heated to 80°C. for 2 h. After cooling down to room temperature, the mixture ispoured into water (20 mL) and extracted with EtOAc (3×20 mL). Theorganic layers are combined and washed with brine and dried (MgSO₄).After filtering off the drying agent, the solvent is removed undervacuum and the residue is purified by flash column chromatography(silica gel, 30%˜80% EtOAc/hexane) to provide the desired product5-amino-1-(tetrahydro-thiopyran-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxylicacid ethyl ester as white solid (300 mg, 59%).

Step B:

5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared from5-amino-1-(tetrahydro-thiopyran-4-yl)-4,5-dihydro-1H-pyrazole-4-carboxylicacid ethyl ester and N-(4-bromo-phenyl)-2-fluoro-benzimidoyl chloride byfollowing the procedure described in example 2. The crude is purified bypreparative LC/MS to provide the titled compound5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid. HPLC-MS calculated for C₂₂H₁₈BrFN₄OS (M+H⁺): 485.0,found: 485.0.

Example 83[5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine

Step A:

A mixture a5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol_fromexample 69 (40 mg, 0.09 mmol) in POCl₃ (0.5 mL) is heated to 80° C. for2 h. The reaction mixture is then cooled down to room temperature andconcentrated. The residue is used directly for next step withoutpurification.

Step B:

4-Chloro-5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridinefrom step A (15 mg, 0.033 mmol) is treated with dimethylamine (2 M inTHF, 1 mL, 2 mmol) in a sealed tube at 100° C. for 14 h. After coolingdown to room temperature, the mixture is concentrated and the residue ispurified by flash column chromatography (silica gel, 0%˜15% EtOAc/hex)to provide the titled compound[5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine(11 mg, 73%). ¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.32 (d, 2H), 7.47(t, 2H), 7.27 (t, 1H), 7.23 (d, 2H), 7.16 (d, 2H), 7.11 (d, 2H), 7.03(d, 2H), 2.91 (s, 6H); HPLC-MS calculated for C₂₆H₂₀Cl₂N₄ (M+H⁺): 459.1,found: 459.1.

Example 845-(4-Bromo-phenyl)-1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(5 mg, 0.01 mmol) in CHCl₃ (0.5 mL) is added m-CPBA (9 mg) at 0° C.After the mixture is stirred at 0° C. for 1 h, it is treated withsaturated aqueous NaHCO₃ solution (1 mL) and extracted with EtOAc (3×2mL). The organic layers are combined and concentrated. The residue ispurified by preparative thin layer chromatography (silica gel, 40%EtOAc/hex) to provide the titled compound5-(4-bromo-phenyl)-1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid (3.5 mg, 68%). ¹H NMR (CDCl₃) δ (ppm) 8.18 (s, 1H), 7.40(d, 2H), 7.34 (qd, 1H), 7.28 (d, 1H), 7.12 (t, 1H), 7.00 (bd, 2H), 6.92(t, 1H), 5.07 (m, 1H), 3.58 (td, 2H), 3.13 (td, 2H), 2.75-2.82 (m, 2H),2.53-2.59 (m, 2H); HPLC-MS calculated for C₂₂H₁₈BrFN₄O₃S (M+H⁺): 517.0,found: 517.0.

Example 855-(4-Chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A solution of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid methyl ester (50 mg, 0.11 mmol) in dioxane is added NaOH (1 N, 400μL, 0.4 mmol) and stirred at room temperature for 14 h. The mixture isthen neutralized by adding HCl (1 N, 400 μL, 0.4 mmol) and concentrated.The resulted residue is treated with SOCl₂ (1 mL) at room temperaturefor 1 h and excess SOCl₂ is removed under vacuum. The residue isdissolved in CH₂Cl₂ and added N-hydroxy-acetamidine (12 mg, 0.16 mmol)followed by Et₃N (17 mg, 0.16 mmol). After stirring at room temperaturefor 1 h, the mixture is treated with water (2 mL) and extracted withEtOAc (3×2 mL). The organic layers are combined and concentrated, theresidue is dissolved in EtOH (4 mL), NaOAc (40 mg) is added and themixture is heated to 80° C. for 5 h. After cooling down to roomtemperature, the solvent is removed and the residue is purified bypreparative LC/MS to provide the titled compound5-(4-chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.12 (d, 2H), 8.01 (d, 2H),7.48-7.54 (m, 4H), 7.37 (t, 1H), 7.32 (d, 2H), 7.10 (d, 2H), 2.47 (s,3H); HPLC-MS calculated for C₂₆H₁₇ClN₆O₂ (M+H⁺): 481.1, found: 481.1.

Example 865-(4-Chloro-phenyl)-6-(4-isoxazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

A mixture of6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(50 mg, 0.11 mmol) and N,N-dimethylformamide dimethyl acetal (1 mL) isheated at 80° C. for 14 h. After cooling down to room temperature,excess N,N-dimethylformamide dimethyl acetal is removed under vacuum toprovide5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas yellow solid (56 mg, 100%). HPLC-MS calculated for C₂₈H₂₂ClN₅O₂(M+H⁺): 496.2, found: 496.2.

Step B:

To a slurry of5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(8.0 mg, 0.016 mmol) in MeOH (0.5 mL) is added NH₂OH.HCl (1.5 mg, 0.022mmol). The mixture is heated to 80° C. for 2 h and cooled down to roomtemperature. After concentration under vacuum, the residue is purifiedby preparative LC/MS to provide the titled compound5-(4-Chloro-phenyl)-6-(4-isoxazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid. HPLC-MS calculated for C₂₆H₁₆ClN₅O₂ (M+H⁺): 466.1,found: 466.1.

Example 875-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a suspension of5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(11 mg, 0.022 mmol) in MeOH (0.5 mL) is added hydrazine hydrate (2.0 mg,0.04 mmol) and HCl (4 M in dioxane, 10 μL, 0.04 mmol). The mixture isheated to 80° C. for 2 h and cooled down to room temperature. Themixture is concentrated and purified by preparative LC/MS to provide thetitled compound5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one_aswhite solid. HPLC-MS calculated for C₂₆H₁₇ClN₆O (M+H⁺): 465.1, found:465.1.

Example 886-(4-Acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Method 1

A solution of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid methyl ester (450 mg, 0.98 mmol) in dioxane (6 mL) is added NaOH (2N, 1.5 mL, 3 mmol) and stirred at room temperature for 14 h. The mixtureis then concentrated and treated with SOCl₂ (4 mL) at room temperaturefor 1 h. The excess SOCl₂ is removed under vacuum and flushed withtoluene (2×2 mL). The resulted residue is dissolved in CH₂Cl₂ (3 mL) andslowly dropped into a solution of freshly prepared Me₂CμLi (2.0 mmol) inEt₂O (4 mL) at −78° C. The mixture is kept at the same temperature for 1h. when MeOH (1 mL) is added to quench the reaction. The mixture is thenallowed to warm up to room temperature and treated with saturatedaqueous NH₄Cl solution (20 mL). After extraction with EtOAc (3×15 mL),the organic layers are combined, washed with brine and dried (MgSO₄).After filtering off the drying agent, the solvent is removed undervacuum and the residue is purified by flash column chromatography(silica gel, 0%˜50% EtOAc/hexane) to provide the titled compound6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.HPLC-MS calculated for C₂₅H₁₇ClN₄O₂ (M+H⁺): 441.1, found: 441.1.

Method 2

To a reaction tube charged with6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(20 mg, 0.042 mmol), butylvinyl ether (21 mg, 0.21 mmol), Pd(OAc)₂ (1.0mg, 0.004 mmol), 1,3-bis(diphenylphosphino)propane (3.5 mg, 0.008 mmol)and K₂CO₃ (7 mg, 0.05 mmol) is added water (0.05 mL) in DMF (0.5 mL).The system is purged with N₂, sealed and heated to 100° C. for 14 h.After cooling down to room temperature, the mixture is hydrolyzed byadding 1 mL of 1 N HCl for 30 min The mixture is then treated with H₂O(5 mL) and extracted with EtOAc (3×2 mL). The combined extracts isconcentrated and purified by preparative LC/MS to provide the titlecompound6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneand6-[4-(2-butoxy-vinyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(example 360) as a by product (ratio about 1:2). Example 86: HPLC-MScalculated for C₂₅H₁₇ClN₄O₂ (M+1⁺): 441.1, found: 441.1. Example 360:HPLC-MS calculated C₂₉H₂₅ClN₄O₂ (M+1⁺): 497.2, found: 497.2.

Method 3

To a reaction vessel charged with6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(0.5 g, 1.05 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.49 g, 1.36mmol), Pd (PPh₃)₄ (0.061 g, 0.053 mmol) and toluene (5 mL) is purgedwith N₂ and heated to 100° C. for 2 h. After cooling down to roomtemperature, the solvent is removed under vacuum and the residue istreated with acetonitrile (10 mL) and 1 N HCl (40 mL) for 1 h. Themixture is then extracted with EtOAc (3×30 mL) and the combined organiclayer is washed with saturated aqueous KF solution (20 mL). The resultedprecipitate is removed by filtration and washed with EtOAc (2×10 mL).The organic layer is washed with brine and dried (MgSO₄). Afterfiltering off the drying agent, the solvent is removed under vacuum andthe residue is purified by flash column chromatography (silica gel,0%˜50% EtOAc/hexane) to provide the titled compound6-(4-acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(450 mg, 95%). HPLC-MS calculated for C₂₅H₁₇ClN₄O₂ (M+1⁺): 441.1, found:441.1.

Example 894-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzamide

A solution of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid methyl ester (70 mg, 0.153 mmol) in dioxane (1 mL) is added NaOH (2M, 0.25 mL, 0.5 mmol) and stirred at room temperature for 14 h. Themixture is then concentrated and treated with SOCl₂ (1 mL) at roomtemperature for 1 h. The excess SOCl₂ is removed under vacuum andflushed with toluene (2×1 mL). The resulted residue is dissolved inCH₂Cl₂ (1 mL) and dropped into a vigorously stirred ice-cold aqueousNH₄OH solution (30%, 4 mL). After the addition, the mixture is extractedwith EtOAc (3×4 mL). The organic layers are combined and concentrated.The residue is purified by preparative LC/MS to provide the titledcompound4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzamideas white solid. ¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.12 (d, 2H), 7.70(d, 2H), 7.51 (t, 2H), 7.43 (d, 2H), 7.36 (t, 1H), 7.32 (d, 2H), 7.09(d, 2H), 5.99 (b, 1H), 5.63 (b, 1H); HPLC-MS calculated for C₂₄H₁₆ClN₅O₂(M+H⁺): 442.1, found: 442.1.

Example 906-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A suspension of5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(24 mg, 0.048 mmol) in MeOH (1 mL) is treated with guanidinehydrochloride (12 mg, 0.13 mmol) and NaOH (4 mg, 0.1 mmol) at 80° C. for14 h. After cooling down to room temperature, the mixture is treatedwith saturated aqueous NH₄Cl solution (2 mL) and extracted with EtOAc(3×2 mL). The organic layers are concentrated and purified bypreparative thin layer chromatography (silica gel, 2.5% MeOH/CH₂Cl₂) toprovide the titled compound6-[4-(2-amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas a white solid. ¹H NMR (CDCl₃) δ (ppm) 8.35 (b, 1H), 8.34 (s, 1H),8.14 (d, 2H), 7.92 (d, 2H), 7.51 (t, 2H), 7.46 (d, 2H), 7.35 (t, 1H),7.32 (d, 2H), 7.12 (d, 2H), 7.03 (d, 1H), 5.34 (b, 2H); HPLC-MScalculated for C₂₇H₁₈ClN₇O (M+H⁺): 492.1, found: 492.2.

Example 935-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

A mixture of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzamide(20 mg, 0.045 mmol) in N,N-dimethylformamide dimethyl acetal (0.5 mL) isheated to 120° C. for 1.5 h. and cooled down to room temperature. Theexcess of N,N-dimethylformamide dimethyl acetal is removed under vacuumto provide the desired product4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamidewithout further purification. HPLC-MS calculated for C₂₇H₂₁ClN₆O₂(M+H⁺): 497.1, found: 497.1.

Step B:

A mixture of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide(7.0 mg, 0.014 mmol) and hydrazine hydrate (5 mg, 0.1 mmol) in aceticacid (200 μL) is stirred at 90° C. for 1 h and cooled down to roomtemperature. The solvent is removed under vacuum and residue is treatedwith saturated aqueous NaHCO₃ solution (1 mL) and extracted with EtOAc(3×2 mL). The organic layers are combined and concentrated. The residueis purified by preparative thin layer chromatography (silica gel, 2%MeOH/CH₂Cl₂) to provide the titled compound5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid (4.8 mg, 73%). ¹H NMR (CDCl₃) δ (ppm) 8.40 (s, 1H), 8.34(s, 1H), 8.15 (d, 2H), 8.03 (d, 2H), 7.51 (t, 2H), −7.45 (d, 2H), 7.34(t, 1H), 7.31 (d, 2H), 7.11 (d, 2H); HPLC-MS calculated for C₂₅H₁₆ClN₇O(M+H⁺): 466.1, found: 466.1.

Example 945-(4-Chloro-phenyl)-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-N-dimethylaminomethylene-benzamide(10 mg, 0.02 mmol) in acetic acid (200 mL) is added a mixture ofNH₂OH.HCl (5 mg, 0.072 mmol) in NaOH (1 M, 50 μL, 0.05 mmol)). Themixture is stirred at 90° C. for 1 h. and cooled down to roomtemperature. Solvent is removed under vacuum and the residue is treatedwith saturated aqueous NaHCO₃ solution (1 mL) and extracted with EtOAc(3×2 mL). The organic layers are combined and concentrated. The residueis purified by preparative thin layer chromatography (silica gel, 30%EtOAc/hex) to provide the titled compound5-(4-chloro-phenyl)-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid (8 mg, 85%). ¹H NMR (CDCl₃) δ (ppm) 8.50 (s, 1H), 8.35(s, 1H), 8.12 (d, 2H), 8.06 (d, 2H), 7.48-7.54 (m, 4H), 7.37 (t, 1H),7.34 (d, 2H), 7.11 (d, 2H); HPLC-MS calculated for C₂₅H₁₆ClN₆O₂ (M+H⁺):467.1, found: 467.1.

Example 956-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide

6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester (18 mg, 0.033 mmol) in EtOH (1 mL) is treated with LiOH(1 M, 50 μL) at room temperature for 14 h. After removing the solvent,the residue is heated with SOCl₂ (0.5 mL) at 80° C. for 3 h. and cooleddown to room temperature. After removing the excess SOCl₂ under vacuum,the resulted residue is dissolved in anhydrous CH₂Cl₂ and dropped into avigorously stirred ice-cold aqueous NH₄OH solution (30%, 2 mL). Afterthe addition, the mixture is extracted with EtOAc (3×2 mL). The organiclayers are combined and concentrated. The residue is purified bypreparative LC/MS to provide the titled compound6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide. ¹H NMR (CDCl₃) δ (ppm) 10.11 (b, 1H), 8.19 (d, 2H),7.51-7.57 (m, 6H), 7.38-7.47 (m, 8H), 7.18 (d, 2H), 6.65 (b, 1H);HPLC-MS calculated for C₃₀H₂₀ClN₅O₂ (M+H⁺): 518.1, found: 518.1.

Example 966-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester

Step A:

A mixture of 2,3-dicyano-but-2-enedioic acid diethyl ester (3.9 g, 17.6mmol, prepared according to the method reported by C. J. Ireland and J.S. Pizey, J. C.S. Chem. Comm. 1972, 1, 4), phenyl hydrazine (2.28 g,21.1 mmol) and NH₄OAc (135.5 mg, 1.76 mmol) in EtOH (30 mL) is heated to80° C. for 30 min. After cooling down to room temperature, the mixtureis poured into water (200 mL) and extracted with EtOAc (3×50 mL). Theorganic layers are combined and washed with brine and dried (MgSO₄).After filtering off the drying agent, the solvent are removed undervacuum and the residue is purified by flash column chromatography(silica gel, 0%˜50% EtOAc/hex) to provide the desired product3-amino-4-phenyl-cyclopenta-2,5-diene-1,2-dicarboxylic acid diethylester as red oil (2.1 g, 38%). ¹H NMR (CDCl₃) δ (ppm) 7.50-7.55 (m, 4H),7.44 (t, 1H), 5.40 (b, 2H), 4.41 (q, 2H), 4.31 (q, 2H), 1.40 (t, 3H),1.35 (t, 3H); HPLC-MS calculated for C₁₅H₁₇N₃O₄ (M+H⁺): 304.1, found:304.1.

Step B:

6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester is prepared from5-amino-1-phenyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester andN-(4-chloro-phenyl)-biphenyl-4-carboximidoyl chloride by following asimilar procedure as described in example 2 and purified by preparativeLC/MS. ¹H NMR (CDCl₃) δ (ppm) 8.14 (d, 2H), 7.36˜7.57 (m, 12H), 7.33 (d,2H), 7.14 (d, 2H), 4.53 (q, 2H), 1.46 (t, 3H); HPLC-MS calculated forC₃₂H₂₃ClN₄O₃ (M+H⁺): 547.2, found: 547.2.

Example 975-(4-chloro-phenyl)-6-(3′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A microwave reaction tube charged with5-(4-chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(74.9 mg, 0.143 mmol), 3-fluorophenylboronic acid (39.9 mg, 0.285 mmol),and Pd(PPh₃)₄ (16.5 mg, 0.014 mmol) is purged with nitrogen. Toluene(3.5 mL) and Na₂CO₃ aqueous solution (2.0M, 0.75 mL) are added viasyringe. The reaction mixture is heated in a microwave at 170° C. for 20min, and is partitioned between water and ethyl acetate. The organicphase is washed with brine, dried over MgSO₄, concentrated, and purifiedby silica gel chromatography to provide the title compound (37.7 mg, 54%yield) as a white solid product; ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H),8.16 (dd, 2H), 7.52 (t, 2H), 7.48 (d, 2H), 7.43-7.33 (m, 7H), 7.25 (dt,1H), 7.13 (d, 2H), 7.07 (td, 1H); HPLC-MS calculated for C₂₉H₁₈ClFN₄O(M+H⁺) 493.1, found 493.1.

Example 985-(4-chloro-phenyl)-6-(4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A reaction tube charged with5-(4-chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(100.0 mg, 0.191 mmol), Pd₂(dba)₃ (17.5 mg, 0.019 mmol), BINAP (23.7 mg,0.038 mmol), and Cs₂CO₃ (124.2 mg, 0.381 mmol) is purged with nitrogen.Anhydrous toluene (1.0 mL) and morpholine (33.2 mL, 0.381 mmol) areadded via syringe. The reaction mixture is heated at 100° C. overnight,and is partitioned between water and ethyl acetate. The organic phase iswashed with brine, dried over MgSO₄, concentrated, and purified bysilica gel chromatography to provide the title compound (64.3 mg, 70%yield) as a yellow solid product; ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (s,1H), 8.17 (dd, 2H), 7.50 (t, 2H), 7.35 (m, 3H), 7.28 (d, 2H), 7.12 (d,2H), 6.77 (d, 2H), 3.86 (t, 4H), 3.21 (t, 4H); HPLC-MS calculated forC₂₇H₂₂ClN₅O₂ (M+H⁺) 484.1, found 484.1.

Example 995-(4-chloro-phenyl)-6-(4-imidazol-1-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A reaction tube charged with6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(100.0 mg, 0.209 mmol), imidazole (85.5 mg, 1.26 mmol), CuI (4.0 mg,0.021 mmol), (1R,2R)-diaminomethylcyclohexane (6.0 mg, 0.042 mmol), andK₃PO₄ (88.9 mg, 0.429 mmol) is purged with nitrogen. Anhydrous1,4-dioxane (4.0 mL) is added via syringe. The reaction mixture isheated at 100° C. for 5 days, and is partitioned between saturated NH₄Claqueous solution and ethyl acetate. The organic phase is washed withbrine, dried over MgSO₄, concentrated, and purified by silica gelchromatography to provide the title compound (78.7 mg, 81% yield) as awhite solid product; ¹H NMR (CDCl₃, 400 MHz) δ 8.91 (s, 1H), 8.35 (s,1H), 8.10 (dd, 2H), 7.59 (d, 2H), 7.52 (m, 3H), 7.44-7.36 (m, 6H), 7.13(d, 2H); HPLC-MS calculated for C₂₆H₁₇ClN₆O (M+H⁺) 465.1, found 465.1.

If trans-1,2-diaminocyclohexane instead of(1R,2R)-diaminomethylcyclohexane is used as the ligand, a byproduct6-[4-(2-amino-cyclohexylamino)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis also obtained as example 1-(4; HPLC-MS calculated for C₂₉H₂₇ClN₆O(M+H⁺) 511.2, found 511.1.

Example 1005-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A reaction tube charged with6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(40.0 mg, 0.084 mmol) and Pd(PPh₃)₄ (9.7 mg, 0.0084 mmol) is purged withnitrogen. A solution of 2-tributylstannanyl-pyridine (61.6 mg, 0.168mmol) in anhydrous toluene (1.0 mL) is added via syringe. The reactionmixture is heated at 100° C. overnight, and is partitioned between waterand ethyl acetate. The organic phase is washed with brine, concentrated,and purified by preparative LCMS followed by silica gel chromatographyto provide the title compound (18.4 mg, 46% yield) as a white solidproduct; HPLC-MS calculated for C₂₈H₁₈ClN₅O (M+H⁺) 476.1, found 476.1.

Example 1015-(4-chloro-phenyl)-1-phenyl-6-(4-phenyl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

A suspension of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (500 mg,2.46 mmol) in thionyl chloride (2.0 mL) is stirred at room temperaturefor about 15 min before it becomes a clear solution. After removal ofthe solvent, the crude acid chloride is taken in anhydrous DCM (5.0 mL),and transferred dropwise to a solution of 4-chloroaniline (376.7 mg,2.95 mmol) and TEA (1.03 mL, 7.38 mmol) in anhydrous DCM (5.0 mL) at 0°C. The reaction mixture is allowed to warm up to room temperature in anhour and lots of precipitate is generated. After filtration, theprecipitate is washed with water, followed by small amount of DCM, andair-dried to provide crude 5-amino-1-phenyl-1H-pyrazole-4-carboxylicacid (4-chloro-phenyl)-amide (506.2 mg, 66% yield) as a white solidproduct; HPLC-MS calculated for C₁₆H₁₃ClN₄O (M+H⁺) 313.1, found 313.0.

Step B and C:

The crude product from step A is taken in anhydrous pyridine (5.0 mL)and triphosgen (321.8 mg, 1.08 mmol) is added. The mixture is heated at100° C. for 1 h before removal of the solvent. The residue is taken inPOCl₃ (3.0 mL) and heated at 110° C. for 3 h. After removal of POCl₃ invacuo, the residue is taken in cold saturated NaHCO₃ aqueous solutionand extracted with ethyl acetate. The organic phase is washed withbrine, dried over MgSO₄, and evaporated to provide crude6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(408.8 mg, 71% yield) as a grey solid product;

-   HPLC-MS calculated for C₁₇H₁₀Cl₂N₄O (M+H⁺) 357.0, found 357.0.

Step D:

To a solution of crude6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-onefrom step C (20.0 mg, 0.056 mmol) in DCM (1.0 mL) are added1-phenylpiperazine (17.1 μL, 0.112 mmol) and TEA (15.6 μL, 0.112 mmol).The mixture is stirred at room temperature overnight. After removal ofthe solvent, the residue is purified by preparative LCMS to provide thetitle compound; ¹H NMR (CDCl₃, 400 MHz) δ 8.18 (s, 1H), 8.11 (d, 2H),7.52 (m, 4H), 7.38-7.29 (m, 5H), 7.00 (m, 3H), 3.44 (t, 4H), 3.07 (t,4H); HPLC-MS calculated for C₂₇H₂₃ClN₆O (M+H⁺) 483.2, found 483.2.

Example 1026-benzothiazol-2-yl-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A reaction tube charged with6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-Pyrazolo[3,4-d]pyrimidin-4-one(20.0 mg, 0.056 mmol) and Pd(PPh₃)₄ (6.5 mg, 0.0056 mmol) is purged withnitrogen. A solution of 2-tributylstannanyl-benzothiazole (47.6 mg,0.112 mmol) in anhydrous toluene (1.0 mL) is added via syringe. Thereaction mixture is heated at 100° C. for 2 days. After removal of thesolvent, the residue is purified by preparative LCMS to provide thetitle compound; ¹H NMR (CDCl₃, 400 MHz) δ 8.36 (s, 1H), 8.21 (d, 2H),7.90 (t, 1H), 7.69 (t, 1H), 7.59 (t, 2H), 7.46-7.40 (m, 5H), 7.24 (d,2H); HPLC-MS calculated for C₂₄H₁₄ClN₅OS (M+H⁺) 456.1, found 456.1.

Example 1035-(4-chloro-phenyl)-1-phenyl-6-p-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(20.0 mg, 0.056 mmol) in acetonitrile (0.5 mL) are added p-cresol (11.7μL, 0.112 mmol) and K₂CO₃ (15.5 mg, 0.112 mmol). The mixture is heatedat 100° C. overnight. K₂CO₃ is then filtered off. The filtrate isconcentrated and purified by preparative LCMS to provide the titlecompound; ¹H NMR (CDCl₃, 400 MHz) δ 8.20 (s, 1H), 7.91 (dd, 2H), 7.54(d, 2H), 7.32 (m, 4H), 7.22 (m, 3H), 7.03 (d, 2H), 2.39 (s, 3H); HPLC-MScalculated for C₂₄H₁₇ClN₄O₂ (M+H⁺) 429.1, found 429.2.

Example 1046-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

Step A:

4-Amino-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester is preparedfrom benzyl cyanide and ethyl diazoacetate, using the conditiondescribed in Rochais, C.; Lisowski, V.; Dellemagne, P.; Rault, S.Tetrahedron Lett. 2004, 45, 6353. HPLC-MS calculated for C₁₂H₁₃N₃O₂(M+H⁺) 232.1, found 232.2.

Step B:

6-(4-Bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-oneis prepared as described in Example 2, using4-amino-5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester from step Ainstead of ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate. ¹H NMR (CDCl₃,400 MHz) δ 8.41 (dd, 2H), 7.48 (m, 4H), 7.39 (t, 1H), 7.21 (d, 2H), 7.05(m, 4H), 2.32 (s, 3H); HPLC-MS calculated for C₂₄H₁₇BrN₄O (M+H⁺) 457.1,found 457.1.

Example 1215-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine

To a solution of2-[5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethanol(13 mg, 0.025 mmol, prepared in 84% yield as described in Example 5except using ethylene glycol as solvent.) in anhydrous CH₂Cl₂ (0.5 mL)is added CH₃SO₂Cl (5 μL) followed by Et₃N (20 After the addition, themixture is stirred at room temperature for 2 h. and morpholine (20 μL)is added. After the resulted mixture is stirred at 60° C. for 10 h. itis cooled down to room temperature and treated with water (4 mL) andextracted with EtOAc (3×3 mL). The organic layers are combined andconcentrated. The residue is purified by preparative LC/MS to providethe titled compound5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine.HPLC-MS calculated for C₃₀H₂₅Cl₃N₄O₂ (M+H⁺): 579.1 found: 579.1.

Example 1649-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-oneStep 1: Preparation of 5-Amino-1-benzyl-1H-imidazole-4-carboxylic acidethyl ester

A solution of amino-cyano-acetic acid ethyl ester (1.2 g, 9.38 mmol) andtriethyl orthoformate (1.56 mL, 9.38 mmol) in acetonitrile (10 mL) isheated at reflux for 45 min. After cooled down to room temperature,benzylamine (1.1 mL, 9.85 mmol) is added. Stirred at room temperature,solid precipitated out. Filtration gives a white solid as product (twosteps yield 51%). 1H NMR (CDCl3) μ 7.37 (m, 3H), 7.15 (d, 3H), 4.99 (s,2H), 4.68 (b, 2H), 4.34 (q, 2H), 1.39 (t, 3H); m/z 246.1 (M+H⁺).

Step 2:1-Benzyl-5-[bis-(2,4-dichloro-benzoyl)-amino]-1H-imidazole-4-carboxylicacid ethyl ester

A suspension of 5-amino-1-benzyl-1H-imidazole-4-carboxylic acid ethylester (1.15 g, 4.69 mmol) and triethylamine (1.96 mL, 14.1 mmol) in 20mL of dichloromethane is cooled to 0° C. 2,4-Dichlorobenzoyl chloridesolution (1.65 mL, 11.7 mmol in 5 mL of dichloromethane) is then addeddropwise. After addition, the reaction mixture is warmed to roomtemperature for 1 h before quenched with water. The organic phase isseparated and the aqueous phase is extracted with dichloromethane. Theorganic phases are combined and dried over magnesium sulfate.Concentration followed by purification with flash chromatography givesthe desired compound as a pale yellow solid (1.5 g, yield 55%). 1H NMR(CDCl₃) δ 7.57 (d, 2H), 7.38 (m, 4H), 7.31 (d, 2H), 7.21 (m, 4H), 5.12(s, 2H), 4.41 (q, 2H), 1.41 (t, 3H); m/z 590.0 (M+H⁺).

Step 3: 1-Benzyl-5-(2,4-dichloro-benzoylamino)-1H-imidazole-4-carboxylicacid (4-chloro-phenyl)-amide

A dry flask charged with 4-chloroanaline (390 mg, 3.05 mmol) andtetrahydrofuran (6 mL) is cooled to 0° C. n-Butyllithium solution (1.6 Min hexanes) is added dropwise. The reaction mixture is warmed to roomtemperature for 10 min before cooled down again to 0° C. The resultingsolution is cannulated a solution of1-benzyl-5-[bis-(2,4-dichloro-benzoyl)-amino]-1H-imidazole-4-carboxylicacid ethyl ester (300 mg, 0.51 mmol) in tetrahydrofuran. After addition,the reaction mixture is stirred at room temperature for 2 h. 1 M HCl isadded after the reaction quenched with water. The organic phase isseparated and the aqueous phase is extracted with ethyl acetate. Theorganic phases are combined and dried over magnesium sulfate.Concentration followed by purification with flash chromatography givesthe desired product (81 mg, 32% yield). 1H NMR (CDCl₃) δ 9.01 (s, 1H),8.86 (s, 1H), 7.59 (m, 3H), 7.47 (d, 1H), 7.35 (m, 4H), 7.27 (m, 3H),7.18 (m, 2H), 5.35 (s, 2H); m/z 499.0 (M+H⁺).

Step 4:9-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one

The reaction mixture of1-benzyl-5-(2,4-dichloro-benzoylamino)-1H-imidazole-4-carboxylic acid(4-chloro-phenyl)-amide (60 mg, 0.12 mmol), triethylamine (670 μL, 4.8mmol) and trimethylsilyl chloride (303 μL, 2.4 mmol) is heated at 100°C. for 2 days. After cooled to room temperature, the resulting mixtureis quenched with 1 N HCl and dichloromethane. The aqueous phase isextracted with dichloromethane. The organic phases is combined, ishedwith brine and dried over magnesium sulfate. Concentration followed bypurification with chromatography gives the desired product (41 mg, 71%yield).

Example 1661-(4-Bromo-phenyl)-9-cyclopropyl-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-oneStep 1: 5-Amino-1-cyclopropyl-1H-imidazole-4-carboxylic acid ethyl ester

A solution of amino-cyano-acetic acid ethyl ester (333 mg, 2.6 mmol) andtriethyl orthoformate (454 μL, 2.73 mmol) in acetonitrile is heated atreflux for 45 min After cooled down to room temperature,cyclopropylamine (180 μL, 2.6 mmol) is added. After stirred at roomtemperature overnight, the solution is concentrated and purified withchromatography. The desired product is obtained a white solid as product(290 mg, 57% yield). ¹H NMR (CDCl₃) δ 7.08 (s, 1H), 5.01 (b, 2H), 4.27(q, 2H), 2.95 (m, 1H), 1.31 (t, 3H), 1.04 (m, 2H), 0.91 (m, 2H); m/z196.1 (M+H⁺).

Step 2: N-(4-Bromo-phenyl)-2,4-dichloro-benzimidoyl chloride

To a solution of 4-bromoaniline (40 mg, 0.12 mmol) and 2,4-dichlorobenzoyl chloride (69 μL, 0.12 mmol) in dichloromethane is addedtriethylamine (20 μL, 0.144 mmol). After sttired at room temperature for30 min, the solvent is removed. The residue is added 0.5 mL of thionylchloride. The reaction mixture is heated at 80° C. for 1 h,concentrated. The product is used in the next step reaction.

Step 3:1-(4-Bromo-phenyl)-9-cyclopropyl-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one

A similar method as making compound 77 gives the desired product afterpurification with HPLC. HPLC-MS calculated for C₂₀H₁₃BrCl₂N₄O (M+H⁺):474.9, found 474.9.

Example 1681-(4-Chloro-phenyl)-9-phenyl-2-(4-thiophen-3-yl-phenyl)-1,9-dihydro-purin-6-one

A solution of1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(20 mg, 0.038 mmol), 3-thiophene boronic acid (9.7 mg, 0.076 mmol) andtetrakis(triphenylphosphine) palladium (4.4 mg, 0.0038 mmol) in 1 mL oftoluene is added 2.0 M Na₂CO₃ solution (200 μL). The reaction mixture isheated at 170° C. on the microwave oven for 20 min After cooled down,the resulting solution is concentrated and purified with HPLC. ¹H NMR(CDCl₃) δ (ppm) 8.12 (s, 1H), 7.71 (d, 2H), 7.57 (t, 2H), 7.47 (m, 4H),7.38 (m, 1H), 7.33 (m, 5H), 7.14 (d, 2H); HPLC-MS calculated forC₂₇H₁₇ClN₄OS (M+H⁺): 481.0, found 481.0.

Example 1711-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-4-yl-phenyl)-1,9-dihydro-purin-6-one

A dry flask charged with1-(4-chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(20 mg, 0.038 mmol), 4-tributylstannylpyridine (14 mg, 0.038 mmol) andtetrakis(triphenylphosphine) palladium (4.4 mg, 0.0038 mmol) is heatedat 100° C. overnight. Filtration and concentration followed bypurification gives the desired product. ¹H NMR (methanol-d₄) δ (ppm)8.69 (d, 2H), 8.49 (s, 1H), 8.04 (d, 2H), 7.81 (m, 4H), 7.60 (m, 4H),7.51 (m, 1H), 7.35 (m, 4H); HPLC-MS calculated for C₂₈H₁₈ClN₅O (M+H⁺):476.2, found 476.2.

Example 174 1,2-Bis-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one

A mixture of phenylboronic acid (18.7 mg, 0.15 mmol), purinone (30 mg,0.077 mmol) and [Cu(OH)TMEDA]₂Cl₂ (17.8 mg, 0.039 mmol) in drydichloromethane is stirred at room temperature overnight. Celitefilteration to remove copper salt and concentrate the filterate topurify by column chromatography to give N-7 phenyl purinone as a majorproduct. HPLC-MS calculated for C₂₃H₁₄Cl₂N₄O (M+H⁺): 433.1, found 433.1

Example 2551-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one

5-Amino-2-ethyl-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester: Asolution of amino-cyano-acetic acid ethyl ester (400 mg, 3.12 mmol) andtriethyl orthopropionate (629 μL, 3.12 mmol) in acetonitrile is heatedat reflux for 45 minutes. After cooled down to room temperature, aniline(285 μL, 3.12 mmol) is added. After stirred at room temperatureovernight, the solution is concentrated and purified with flashchromatography. A pale yellow solid is obtained as the desired product:¹H NMR (CDCl₃) δ 7.56 (m, 3H), 7.29 (m, 2H), 4.77 (b, 2H), 4.37 (q, 2H),2.49 (q, 2H), 1.40 (t, 3H), 1.11 (t, 3H); m/z 260.1 (M+1).

1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one:A similar method using in making compound in example 77 is used to makethe desired product: ¹H NMR (CDCl₃) δ (ppm) 7.58 (m, 3H), 7.43 (m, 6H),7.31 (d, 2H), 7.02 (d, 2H), 2.84 (q, 2H), 1.32 (t, 3H); HPLC-MScalculated for C₂₆H₁₈BrF₃N₄O (M+H⁺): 539.1, found 539.1.

Example 2705-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(50.0 mg, 0.107 mmol) is dissolved in 3 mL of acetic anhydride.Concentrated nitric acid (300 μL, 4.74 mmol) is added dropwise to thereaction mixture at room temperature. A mild temperature increaseoccurred upon addition of the acid. The reaction mixture is brieflyheated just to boil and allowed to cool to room temperature. Thereaction mixture is poured onto ice/sodium bicarbonate mixture andextracted with dichloromethane. Ortho and para isomers are separated bycolumn chromatography: ¹H NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 8.07 (d,1H), 7.87 (d, 1H), 7.79 (t, 1H), 7.61 (t, 1H), 7.33-7.27 (m, 4H), 7.22(d, 2H), 6.97 (d, 1H). HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O₃ (M+H⁺)512.0, found 512.0.

Example 2711-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(100 mg, 0.195 mmol) is dissolved in 20 mL of dioxane. Platinumoxide(11.0 mg, 0.0484 mmol) was added as a slurry in 2 mL of water to thereaction mixture under a nitrogen atmosphere. The mixture was placedunder balloon pressure of hydrogen and the reaction is completed within1 h. The solids are filtered off and the solution is concentrated.Purification by reverse phase HPLC affords the title compound. ¹H NMR(DMSO, 400 MHz) δ 8.78 (s, 1H), 8.15 (d, 2H), 7.97-7.95 (m, 2H), 7.90(m, 3H), 7.84 (dd, 1H), 7.78 (m, 1H), 7.30 (d, 2H), 6.00 (s, 2H).HPLC-MS calculated for C₂₃H₁₄Cl₃N₅O (M+H⁺) 482.0, found 482.0.

Example 2765-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-(4-methyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-Amino-3-(4-methyl-piperazin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylicacid ethyl ester is prepared as follow. Commercially available2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester (2.18 g, 10.0mmol) is dissolved in 100 mL of dry ethanol and 1-methyl-piperazine (1.0g, 10 mmol) is added and the reaction is heated to reflux for 1.5 h.Phenylhydrazine (1.19 g, 10 mmol) is added via syringe and the reactionmixture is heated to reflux overnight. The solvent is evaporated and theresulting solid is purified by flash chromatography to yield 360 mg ofthe desired product as well as 800 mg of5-Amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethylester. ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (m, 4H), 7.35 (m, 1H), 4.35 (q,2H), 3.38 (m, 4H), 2.65 (m, 4H), 2.39 (s, 3H), 1.39 (t, 3H). HPLC-MScalculated for C₁₇H₂₃N₅O₂ (M+H⁺) 330.18, found 330.18. The titlecompound of Example 276 was prepared from this material following theprocedures described in Example 1. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (d,2H), 7.33 (t, 3H), 7.20 (d, 2H), 7.06 (m, 2H), 6.90 (m, 1H), 3.74 (m,4H), 2.67 (m, 4H), 2.37 (broad s, 3H). HPLC-MS calculated forC₂₈H₂₃Cl₃N₆O (M+H⁺) 565.1, found 565.1.

Example 2775-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Preparation of5-Amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethylester: Commercially available 2-Cyano-3,3-bis-methylsulfanyl-acrylicacid ethyl ester (2.18 grams, 10 mmol) is dissolved in 100 mL of dryethanol. Phenylhydrazine (1.19 g, 10.0 mmol) is added via a syringe andthe reaction mixture is heated to reflux for 3 h. The solvent is thenremoved and the resulting solid is recrystallized from CH₂Cl₂ yielding2.5 g of final product. 1H NMR (CDCl3, 400 MHz) δ 7.54 (m, 4H), 7.40 (m,1H), 4.35 (q, 2H), 2.55 (s, 3H), 1.41 (t, 3H). HPLC-MS calculated forC₁₃H₁₅N₃O₂S (M+H⁺) 278.1, found 278.1.

The title compound of Example 277 is prepared from5-Amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethylester following the procedures described Example 1. 1H NMR (CDCl3, 400MHz) δ 8.08 (d, 2H), 7.47 (m, 4H), 7.33 (m, 2H), 7.18 (m, 3H), 6.95 (m,1H), 2.73 (s, 3H). HPLC-MS calculated for C₂₄H₁₅BrCl₂N₄OS (M+H⁺) 557.0,found 557.0.

Example 2785-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(200 mg, 0.358 mmol) is dissolved in 10 mL of dichloromethane. mCPBA(254 mg, 1.07 mmol) is added and the reaction mixture is stirredovernight. The reaction mixture is workuped with aqueous sodiumbicarbonate and purified by flash chromatography. ¹H NMR (CDCl₃, 400MHz) δ 8.05 (d, 2H), 7.59-7.40 (m, 5H), 7.35 (m, 1H), 7.21 (dd, 2H),7.16 (d, 1H), 6.98 (m, 1H), 3.54 (s, 3H). HPLC-MS calculated forC₂₄H₁₅BrCl₂N₄O₃S (M+H⁺) 591.0, found 591.0.

Example 2805-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-hydroxymethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoicacid (115 mg, 0.225 mmol) is dissolved in 6 mL of THF. To the solutionTEA (68.0 mg, 0.674 mmol) and isobutylchloroformate (46.0 mg, 0.337mmol) are added and the mixture is stirred for 1.5 h. The resultingmixture is added to a solution of sodium borohydride (33.3 mg, 0.898mmol) in 3 mL of water and then stirred for 3 h, concentrated, andextracted with water/ethyl acetate and purified by columnchromatography. ¹H NMR (dioxane, 400 MHz) δ 8.33 (s, 1H), 8.00 (d, 2H),7.45 (s, 1H), 7.39 (d, 2H), 7.16 (d, 1H), 7.29-7.19 (m, 5H), 7.03 (m,1H), 4.53 (d, 2H), 3.71 (t, 1H). HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂(M+H⁺) 497.0, found 497.0.

Example 2815-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoicacid (54.1 mg, 0.106 mmol) is dissolved in 1 mL of thionyl chloride andstirred for 1 h at reflux. The thionyl chloride is then removed under astream of dry nitrogen and the resulting solid is dissolved in 2 mL ofdry dichloromethane. N-methylpiperazine (500 mg, 5.00 mmol) is thenadded to the solution and the reaction mixture is stirred for 2 h. Afterthe volatiles are evaporated, the resulting residue is dissolved in 1 MNaOH and extracted with ethyl acetate. The crude product is purified bycolumn chromatography. ¹H NMR (CDCl₃,400 MHz) δ 8.36 (s, 1H), 8.28 (d,2H), 7.57 (d, 2H), 7.36-7.29 (m, 3H), 7.23-7.16 (m, 2H), 7.03 (m, 1H),3.97 (m, 3H), 3.48 (m, 2H), 2.83 (m, 6H). HPLC-MS calculated forC₂₉H₂₃Cl₃N₆O₂ (M+H⁺) 593.1, found 593.1.

Example 2845-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-hydroxymethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(90.0 mg, 0.181 mmol) is dissolved in 10 mL of CH₂Cl₂.Trichloroisocyanuric acid (42.0 mg, 0.181 mmol) and TEMPO (1 mg) areadded sequentially to the reaction mixture. The reaction mixture isallowed to stir for 30 min and the organic layer is washed with sodiumbicarbonate and water, thus resulting in pure aldehyde. A portion of thealdehyde (40.0 mg, 0.0807 mmol) is dissolved in 2 mL of dry methanol.200 μL of acetic acid and 100 μL of N-methylpiperazine are added to thereaction mixture and the mixture is allowed to stir for 10 min at roomtemp. Sodium cyanoborohydride (15 mg, 0.238 mmol) is added and thereaction mixture is stirred for 10 min and then quenched with ammoniumhydroxide. The crude material is purified by column chromatography. ¹HNMR (CDCl₃,400 MHz) δ 8.34 (s, 1H), 8.06 (d, 2H), 7.44 (m, 2H),7.34-7.28 (m, 3H), 7.18 (m, 2H), 7.03 (m, 1H), 5.31 (s, 2H), 3.66 (m,2H), 2.89 (m, 6H), 2.71 (s, 3H). HPLC-MS calculated for C₂₉H₂₅Cl₃N₆O(M+H⁺) 579.1, found 579.1.

Example 2871-(4-Chloro-phenyl)-8-(ethyl-methyl-amino)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one

Step A:

1-(4-Chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one(50.0 mg, 0.107 mmol) and sodium acetate (300 mg) are dissolved in 10 mLof acetic acid. 250 μLs of bromine is added and the reaction mixture isstirred for 3 h. After the volatile is evaporated, the residue ispartitioned with DCM and water. The organic layer is collected andevaporated to dryness. The crude material is purified by columnchromatography, yielding 78 mg (84%) of8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one.¹H NMR (DMSO, 400 MHz) δ 7.63 (m, 5H), 7.57 (d, 2H), 7.50 (d, 2H), 7.43(d, 2H), 7.39 (d, 2H). HPLC-MS calculated for C₂₄H₁₃BrClF₃N₄O (M+H⁺)545.0, found 545.0.

Step B:

8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one(19.0 mg, 0.0348 mmol), potassium carbonate (400 mg, 2.89 mmol), andethyl-methyl-amine (172 mg, 2.91 mmol) are mixed in a microwave tubewith 1 mL of dry acetonitrile. The tube is then capped and heated to200° C. for 40 min in a microwave reactor. Then the reaction mixture isdiluted with CH₂Cl₂ and filtered. The filtrate is evaporated and thecrude product is purified by column chromatography, yielding 9 mg (49%)of the title compound. ¹H NMR (CDCl₃,400 MHz) δ 7.54 (m, 4H), 7.47 (m,1H), 7.42 (d, 2H), 7.30 (d, 4H), 7.08 (d, 2H), 3.17 (q, 2H), 2.90 (s,3H), 1.03 (t, 3H). HPLC-MS calculated for C₂₇H₂₁ClF₃N₅O (M+H⁺) 524.1,found 524.1.

Example 2891-(4-Chloro-phenyl)-6-oxo-9-phenyl-2-(4-trifluoromethyl-phenyl)-6,9-dihydro-1H-purine-8-carbonitrile

8-Bromo-1-(4-chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one(10.0 mg, 0.0183 mmol), potassium cyanide (110 mg, 1.68 mmol) and18-crown-6 (12.0 mg, 0.0454 mmol) are added to a microwave tube with 1mL of dry acetonitrile. The tube is capped and heated to 200° C. for 45min in microwave reactor. The reaction mixture is then filtered and thefiltrate is evaporated to dryness. The crude material is purified bycolumn chromatography, yielding 6.2 mg (69%) of the title compound. ¹HNMR (CDCl₃,400 MHz) δ 7.64 (m, 5H), 7.52 (d, 2H), 7.38 (m, 4H), 7.12 (d,2H). HPLC-MS calculated for C₂₅H₁₃ClF₃N₅O (M+H⁺) 492.1, found 492.1.

Example 2971-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-methoxy-9-phenyl-1,9-dihydro-purin-6-one

A microwave tube is charged with sodium hydride (24.0 mg, 1.0 mmol) anddry methanol. After the reaction mixture is stirred for 3 min,8-Bromo-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(8.0 mg, 0.015 mmol) is added. The tube is then capped and the mixtureis heated in an oil bath for 3 h at 80° C. The reaction mixture isworked up by evaporating the solvent. The crude material is purified byflash chromatography. 1H NMR (CDCl3, 400 MHz) δ 7.63 (m, 4H), 7.43 (m,1H), 7.28 (m, 4H), 7.11 (d, 2H), 7.03 (m, 1H), 4.25 (s, 3H). HPLC-MScalculated for C24H15Cl3N4O2 (M+H+) 497.0, found 497.0.

Example 3036-(4-bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

Step A:

4-Amino-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester isprepared from acetophenone, using the condition described in Yuan, J.;Gulianello, M.; De Lombaert, S.; Brodbeck, R.; Kieltyka, A.; Hodgetts,K. J. Bioorg. Med. Chem. Lett. 2002, 2133; HPLC-MS calculated forC₁₃H₁₅N₃O₂ (M+H⁺) 246.1, found 246.1.

Step B:

6-(4-Bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-oneis prepared as described in Example 2, using4-amino-1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester fromstep A instead of ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate; ¹H NMR(CDCl₃, 400 MHz) δ 7.66 (d, 2H), 7.54 (t, 2H), 7.47 (t, 1H), 7.43 (d,2H), 7.13 (d, 2H), 7.03 (d, 2H), 6.98 (d, 2H), 4.19 (s, 3H), 2.26 (s,3H); HPLC-MS calculated for C₂₅H₁₉BrN₄O (M+H⁺) 471.1, found 471.1.

Alternatively,6-(4-Bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-onecan also be prepared as a minor by-product as to be described in Example304.

Example 3046-(4-bromo-phenyl)-1-methyl-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

To a solution of6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one(11.0 mg, 0.024 mmol) in acetonitrile (0.3 mL) are added K₂CO₃ (6.6 mg,0.048 mmol) and MeI (5.99 μL, 0.096 mmol). The reaction mixture isstirred at room temperature for overnight before the removal of K₂CO₃ byfiltration. The filtrate is concentrated and purified by preparativeLC/MS to provide the title compound; ¹H NMR (CDCl₃, 400 MHz) δ 8.36 (d,2H), 7.47 (t, 2H), 7.44 (d, 2H), 7.35 (t, 1H), 7.22 (d, 2H), 7.04 (m,4H), 4.37 (s, 3H), 2.31 (s, 3H); HPLC-MS calculated for C₂₅H₁₉BrN₄O(M+H⁺) 471.1, found 471.1.

6-(4-Bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-onein Example 303 is also prepared in this reaction as a minor by-product.

Example 3056-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-1-methanesulfonyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one

To a solution of6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one(20.0 mg, 0.045 mmol) in DCM (0.5 mL) are added MsCl (7.05 μL, 0.091mmol) and TEA (12.64 μL, 0.091 mmol). The reaction mixture is stirred atroom temperature for overnight before removal of the solvent. Theresidue is purified by preparative LC/MS to provide the title compound;¹H NMR (CDCl₃, 400 MHz) δ 8.47 (dd, 2H), 7.48 (m, 3H), 7.34 (d, 2H),7.28 (d, 2H), 7.14 (m, 4H), 3.77 (s, 3H), 2.87 (m, 1H), 1.22 (s, 3H),1.21 (s, 3H); HPLC-MS calculated for C₂₇H₂₃ClN₄O₃S (M+H⁺) 519.1, found519.1.

Example 3066-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylicacid dimethylamide

To a solution of6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one(20.0 mg, 0.045 mmol) in anhydrous pyridine (0.3 mL) is addeddimethylcarbamyl chloride (41.6 μL, 0.45 mmol). The reaction mixture isstirred at room temperature for overnight before removal of the solvent.The residue is purified by preparative LC/MS to provide the titlecompound; ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (dd, 2H), 7.48 (t, 2H), 7.41(t, 1H), 7.30 (d, 2H), 7.27 (d, 2H), 7.11 (m, 4H), 3.24 (s, 3H), 3.12(s, 3H), 2.86 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculatedfor C₂₉H₂₆ClN₅O₂ (M+H⁺) 512.2, found 512.2.

Example 3115-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(15.0 mg, 0.032 mmol) in DCM (0.3 mL) are added mCPBA (12.0 mg, 77%,0.054 mmol) and NaHCO₃ (9.0 mg, 0.107 mmol). The reaction mixture isstirred at room temperature for overnight before removal of the solvent.The residue is taken in water (1.5 mL) and extracted with ethyl acetate(3×1 mL). The combined ethyl acetate layer is concentrated and purifiedby preparative LC/MS to provide the title compound; ¹H NMR (CDCl₃, 400MHz) δ 8.53 (d, 2H), 8.36 (s, 1H), 8.12 (d, 2H), 7.72 (d, 2H), 7.53 (m,6H), 7.38 (t, 1H), 7.35 (d, 2H), 7.13 (d, 2H); HPLC-MS calculated forC₂₈H₁₈ClN₅O₂ (M+H⁺) 492.1, found 492.1.

Example 3146-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,3-d]pyrimidin-7-one

Step A:

4-Nitro-5-phenyl-isoxazole-3-carboxylic acid ethyl ester is preparedfrom benzoylnitromethane and ethyl chlorooximinoacetate, using thecondition described in Dal Piaz, V.; Pinzauti, S.; Lacrimini, P.Synthesis 1975, 664; ¹H NMR (CDCl₃, 400 MHz) δ 7.93 (d, 2H), 7.65 (t,1H), 7.58 (t, 2H), 4.53 (q, 2H), 1.44 (t, 3H); HPLC-MS calculated forC₁₂H₁₀N₂O₅ (M+H⁺) 263.1, found 263.1.

Step B:

To a solution of 4-nitro-5-phenyl-isoxazole-3-carboxylic acid ethylester (73.0 mg, 0.278 mmol) in EtOH (2.0 mL) is added Raney Ni and themixture is stirred under hydrogen (balloon) for overnight. The reactionmixture is then filtered through Celite and evaporated in vacuo toprovide crude 4-amino-5-phenyl-isoxazole-3-carboxylic acid ethyl ester(61.7 mg, 95% yield); HPLC-MS calculated for C₁₂H₁₂N₂O₃ (M+H⁺) 233.1,found 233.1.

Step C:

A suspension of N-(4-chloro-phenyl)-4-isopropyl-benzamide (20.0 mg,0.073 mmol) in thionyl chloride (0.5 mL) is heated at 80° C. for 1.5 hbefore thionyl chloride is removed in vacuo. The reaction residue isthen taken in anhydrous acetonitrile (1.5 mL), followed by the additionof 4-amino-5-phenyl-isoxazole-3-carboxylic acid ethyl ester from step B(18.7 mg, 0.081 mmol) and anhydrous K₂CO₃ (25.2 mg, 0.182 mmol). Thereaction mixture is heated under nitrogen atmosphere at 180° C. in amicrowave for 2 h, then cooled down to room temperature. K₂CO₃ isremoved by filtration. The filtrate is concentrated and purified bypreparative LC/MS to provide the title compound; ¹H NMR (CDCl₃, 400 MHz)δ 8.37 (dd, 2H), 7.53 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H), 7.11 (m, 4H),2.87 (m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated forC₂₆H₂₀ClN₃O₂ (M+H⁺) 442.1, found 442.2.

Example 3182-[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetamide

Step A:

To[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-aceticacid tert-butyl ester (20.0 mg, 0.036 mmol) are added DCM (0.5 mL) andTFA (0.5 mL). The resultant solution is stirred at room temperature for4 hours. Removal of the solvent under reduced pressure provides crude[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-aceticacid, which is used directly for next reaction without furtherpurification.

Step B:

A solution of the crude[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-aceticacid prepared from previous step, HATU (41.1 mg, 0.108 mmol) and^(i)Pr₂NEt (37.6 μL, 0.216 mmol) in DMF (0.5 mL) is stirred at roomtemperature for 1 hour before transferred dropwise into 7 N ammonia inmethanol solution (1.0 mL) at 0° C. The resultant reaction mixture isstirred at room temperature for 1 hour before removal of the solventunder reduced pressure. The residue is purified by preparative LC/MS toprovide the title compound; HPLC-MS calculated for C₂₈H₂₄ClN₅O₂ (M+H⁺)498.2, found 498.2.

Example 320[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetonitrile

A mixture of2-[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetamide(10.0 mg, 0.020 mmol) and POCl₃ (0.5 mL) is heated at 100° C. for 30minutes. Upon completion, excess POCl₃ is removed under reducedpressure. The residue is purified by preparative LC/MS to provide thetitle compound; HPLC-MS calculated for C₂₈H₂₂ClN₅O (M+H⁺) 480.1, found480.1.

Example 3276-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one

Step A:

A solution of benzoylnitromethane (300.0 mg, 1.82 mmol) and NH₂OH.HCl(126.2 mg, 1.82 mmol) in EtOH (1.5 mL) and acetic acid (0.5 mL) isheated at 100° C. for 7 hours. After cooled down to room temperature,the reaction mixture is taken in H₂O (20 mL) and extracted with ethylacetate (3×10 mL). The combined ethyl acetate layer is dried over MgSO₄and evaporated in vacuo to provide crude 2-nitro-1-phenyl-ethanoneoxime, which is used directly in next step without further purification.

Step B:

To a solution of the crude 2-nitro-1-phenyl-ethanone oxime from previousstep in anhydrous ether (2.0 mL) is added ethyl oxalyl chloride (195.2μL, 1.74 mmol). The reaction mixture is stirred at room temperature forovernight before the addition of TEA (202.6 μL, 1.45 mmol). The reactionmixture is then stirred at room temperature for another 2 days beforeremoval of the solvents. The residue is purified by reverse phase HPLCto provide 4-nitro-3-phenyl-isoxazole-5-carboxylic acid ethyl ester asan oil-like product (299.0 mg, 63% yield); HPLC-MS calculated forC₁₂H₁₀N₂O₅ (M+H⁺) 263.1, found 263.1.

Step C:

To a solution of 4-nitro-3-phenyl-isoxazole-5-carboxylic acid ethylester (62.3 mg, 0.238 mmol) in EtOH (2.0 mL) is added Raney Ni and themixture is stirred under hydrogen (balloon) for overnight. The reactionmixture is then filtered through celite and evaporated in vacuo toprovide crude 4-amino-3-phenyl-isoxazole-5-carboxylic acid ethyl ester(53.3 mg, 97% yield); HPLC-MS calculated for C₁₂H₁₂N₂O₃ (M+H⁺) 233.1,found 233.1.

Step D:

6-(4-Chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-oneis prepared as described in Example 2, using4-amino-3-phenyl-isoxazole-5-carboxylic acid ethyl ester from step Cinstead of ethyl 5-amino-1-phenyl-4-pyrazole-carboxylate, andN-(4-chloro-phenyl)-4-isopropyl-benzamide instead ofN-(4-bromo-phenyl)-4-methyl-benzamide; ¹H NMR (CDCl₃, 400 MHz) δ 8.42(dd, 2H), 7.53 (m, 3H), 7.34 (d, 2H), 7.25 (d, 2H), 7.12 (m, 4H), 2.87(m, 1H), 1.22 (s, 3H), 1.20 (s, 3H); HPLC-MS calculated for C₂₆H₂₀ClN₃O₂(M+H⁺) 442.1, found 442.1.

Example 3306-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

A reaction tube charged with6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(2.85 g, 5.97 mmol), bis(pinacolato)diboron (1.74 g, 6.85 mmol), KOAc(1.76 g, 17.9 mmol), and Pd(dppf)₂Cl₂ (0.15 g, 0.184 mmol) is purgedwith nitrogen. Anhydrous DMF (24.0 mL) is added via syringe. Thereaction mixture is heated at 100° C. for 2 hours, taken in H₂O (300mL), and extracted with ethyl acetate (3×100 mL). The combined organicphase is washed with brine, dried over MgSO₄, concentrated, and purifiedby silica gel chromatography to provide5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(2.50 g, 80% yield) as a white solid product; HPLC-MS calculated forC₂₆H₁₇ClN₆O (M+H⁺) 525.2, found 525.2.

Step B:

A reaction tube charged with5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(500.0 mg, 0.953 mmol), 2-amino-5-bromopyridine (247.3 mg, 1.43 mmol),Cs₂CO₃ (620.8 mg, 1.91 mmol), and Pd(dppf)₂Cl₂ (38.9 mg, 0.048 mmol) ispurged with nitrogen. Anhydrous DMF (9.5 mL) is added via syringe. Thereaction mixture is heated at 100° C. for overnight, cooled down to roomtemperature, then taken in H₂O (100 mL) and ethyl acetate (50 mL). Theinsoluble solid is filtered off and the two layers of the filtrate areseparated. The aqueous layer is extracted with ethyl acetate (2×50 mL).The combined organic phase is washed with brine, dried over MgSO₄,concentrated, and purified by reverse phase HPLC to provide6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(244.2 mg, 52% yield) as a light yellow solid product; ¹H NMR (CDCl₃,400 MHz) δ 8.33 (s, 1H), 8.28 (d, 1H), 8.16 (d, 2H), 7.66 (dd, 1H), 7.51(t, 2H), 7.40 (m, 4H), 7.35 (m, 3H), 7.13 (d, 2H), 6.59 (d, 1H), 4.72(br, 2H); HPLC-MS calculated for C₂₈H₁₉ClN₆O (M+H⁺) 491.1, found 491.1.

Example 3325-(4-chloro-phenyl)-6-[4-(1H-imidazol-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Imidazole (15.6 mg, 0.229 mmol) and MgO (9.2 mg, 0.228 mmol) aresuspended in dry 1,4-dioxane (1.0 mL) and stirred at room temperaturefor 10 minutes to get a homogenous suspension. CuI (14.5 mg, 0.076mmol), Pd(OAc)₂ (0.4 mg, 0.002 mmol) and PPh₃ (2.0 mg, 0.008 mmol) areadded to the reaction mixture. The reaction tube is then sealed andpurged with nitrogen.5-(4-Chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(20.0 mg, 0.038 mmol) is dissolved in dry 1,4-dioxane (0.5 mL), addeddropwise to this solution via syringe, and the mixture is heated at 150°C. for overnight. The mixture is then diluted with ethyl acetate (10 mL)and filtered through celite. The solvents are evaporated in vacuo andthe residue is purified by preparative TLC followed by preparative LC/MSto provide the title compound; HPLC-MS calculated for C₂₆H₁₇ClN₆O (M+H⁺)465.1, found 465.1. Detailed conditions of the C-arylation reaction aredescribed in Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274.

Example 3345-(4-chloro-phenyl)-6-[4-(2-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

4-Bromo-2-methyl-pyridine 1-oxide is prepared from2-methyl-4-nitro-pyridine 1-oxide, using the condition described in U.S.Pat. No. 5,705,499 (Example 67); HPLC-MS calculated for C₆H₆BrNO (M+H⁺)188.0, found 188.0.

Step B:

5-(4-Chloro-phenyl)-6-[4-(2-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared as described in Example 330 (step B), using4-bromo-2-methyl-pyridine 1-oxide from step A instead of2-amino-5-bromopyridine; ¹H NMR (CDCl₃, 400 MHz) δ 8.60 (d, 1H), 8.36(s, 1H), 8.12 (d, 2H), 7.65 (s, 1H), 7.54 (m, 7H), 7.38 (t, 1H), 7.35(d, 2H), 7.13 (d, 2H), 2.73 (s, 3H); HPLC-MS calculated for C₂₉H₂₀ClN₅O₂(M+H⁺) 506.1, found 506.1.

Example 3375-(4-chloro-phenyl)-6-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(28.1 mg, 0.057 mmol) in acetonitrile (0.5 mL) is added a solution ofNaNO₂ (5.4 mg, 0.078 mmol) in H₂O (0.5 mL) at 0° C., followed byaddition of one drop of concentrated H₂SO₄. The reaction mixture is thenheated at 100° C. for 30 minutes, cooled down to 0° C., neutralized bysaturated NaHCO₃ to pH=4-5, and extracted with ethyl acetate. Theorganic layer is concentrated and purified by preparative LC/MS toprovide the title compound; ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.14(d, 2H), 7.91 (dd, 1H), 7.75 (d, 1H), 7.52 (t, 2H), 7.44 (d, 2H), 7.36(m, 5H), 7.13 (d, 2H), 6.88 (d, 1H); HPLC-MS calculated for C₂₈H₁₈ClN₅O₂(M+H⁺) 492.1, found 492.1.

Example 3386-[4-(4-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A reaction tube charged with5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(20.0 mg, 0.038 mmol), 4-amino-2-chloropyridine (9.8 mg, 0.076 mmol),Cs₂CO₃ (24.8 mg, 0.076 mmol), Pd₂(dba)₃ (1.7 mg, 0.002 mmol), and1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride (1.6 mg,0.004 mmol) is purged with nitrogen. Anhydrous 1,4-dioxane (0.5 mL) isadded via syringe. The reaction mixture is heated at 120° C. for 3 days,cooled down to room temperature, taken in H₂O (5 mL), and extracted byethyl acetate (3×3 mL). The combined organic phase is concentrated andpurified by reverse phase HPLC to provide the title compound; ¹H NMR(CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.09 (d, 2H), 8.06 (d, 1H), 7.63 (d,2H), 7.54 (t, 2H), 7.44 (d, 2H), 7.39 (t, 1H), 7.29 (d, 2H), 7.03 (d,2H), 6.89 (s, 1H), 6.59 (d, 1H); HPLC-MS calculated for C₂₈H₁₉ClN₆O(M+H⁺) 491.1, found 491.1.

Example 3406-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid

6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid is prepared from 5-amino-1-phenyl-1H-pyrazole-3,4-dicarboxylic aciddiethyl ester and 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride byfollowing a similar procedure as described in example 2 except that thereaction mixture is heated at 170° C. in a microwave for 45 min insteadof 20 min the crude product is purified by preparative LC/MS to yield6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid as the major product and6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester (example 341) as by product. Example 340: HPLC-MScalculated C₂₄H₁₄BrClN₄O₃ (M+1⁺): 520.0, found: 520.0. Example 341: ¹HNMR (CDCl₃) δ (ppm) 8.10 (d, 2H), 7.50 (t, 2H), 7.41 (m, 3H), 7.34 (d,2H), 7.20 (d, 2H), 7.09 (d, 2H), 4.52 (q, 2H), 1.45 (t, 3H). HPLC-MScalculated C₂₆H₁₈BrClN₄O₃ (M+1⁺): 549.0, found: 549.0.

Example 3426-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide

6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (20 mg, 0.038 mmol) is treated with SOCl2 at 50° C. for 1 h. andcooled down to room temperature. SOCl2 is removed under vacuum and theresidue is dissolved in anhydrous dichloromethane (0.5 mL), MeNH2 (2N inMeOH, 0.2 mL) is added into the solution and the mixture is stirred atroom temperature for 3 h. Solvent is removed under vacuum and theresidue is purified by preparative LC/MS to provide the title compound6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide. 1H NMR (CDCl3) d (ppm) 9.95 (b, 1H), 8.16 (d, 2H),7.51 (t, 2H), 7.41 (m, 5H), 7.22 (d, 2H), 7.13 (d, 2H), 3.05 (d, 3H).HPLC-MS calculated C25H17BrClN5O2 (M+1+): 534.0, found: 534.0.

Example 3476-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid isopropyl ester

6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (20 mg, 0.038 mmol) is treated with SOCl2 (0.5 mL) at 80° C. for 1h and cooled down to room temperature. SOCl2 is removed under vacuum andthe residue is dissolved in anhydrous dichloromethane (0.5 mL),isopropanol (0.05 mL) is added followed by Et3N (0.05 mL). The mixtureis stirred at room temperature for 3 h. Solvent is removed under vacuumand the residue is purified by preparative LC/MS to provide the titlecompound6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid isopropyl ester. 1H NMR (CDCl₃) d (ppm) 8.10 (d, 2H), 7.51 (t, 2H),7.41 (m, 3H), 7.33 (d, 2H), 7.19 (d, 2H), 7.09 (d, 2H), 5.38 (m, 1H),1.44 (d, 6H). HPLC-MS calculated C27H20BrClN4O3 (M+1+): 563.0, found:563.1.

Example 3486-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid tert-butyl ester

A suspension of6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (6 mg, 0.012 mmol) in anhydrous benzene (0.5 mL) is heated to 80°C. when N,N-dimethyl formamide di-tert-butyl acetal (0.02 mL) is added.After the addition, the mixture is stirred at 80° C. for 30 min. Aftercooling down to room temperature, the solvent is removed under vacuumand the residue is purified by preparative LC/MS to provide the titlecompound6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) δ (ppm) 8.12 (d, 2H), 7.50 (t,2H), 7.41 (m, 3H), 7.33 (d, 2H), 7.19 (d, 2H), 7.09 (d, 2H), 1.67 (s,9H). HPLC-MS calculated C₂₈H₂₂BrClN₄O₃ (M+1⁺): 577.1, found: 577.1.

Example 351 5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid (15 mg, 0.031 mmol) is treated with SOCl₂ (0.5 mL) at 80° C. for 1h. and cooled down to room temperature. SOCl₂ is removed under vacuumand the residue is dissolved in anhydrous dichloromethane (0.5 mL).N-hydroxy-acetamidine (9 mg, 0.12 mmol) is added followed by Et₃N (0.02mL). The mixture is stirred at room temperature for 1 h and then pouredinto water (5 mL). The mixture is extracted with EtOAc (3×3 mL). Afterthe combined extracts is concentrated and dried under vacuum for 5 h.,the residue is dissolved in anhydrous dioxane (0.5 mL) followed by theaddition of NaOAc (15 mg). The mixture is stirred at 80° C. for 24 h tocomplete the conversion. After cooling down to room temperature, themixture is treated with water and extracted with EtOAc. The combinedextracts is concentrated and the residue is purified by preparativeLC/MS to provide the title compound5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.¹H NMR (CDCl₃) δ (ppm) 8.21 (d, 2H), 7.54 (t, 2H), 7.42 (t, 1H), 7.32(d, 2H), 7.29 (d, 2H), 7.12 (m, 4H), 2.87 (m, 1H), 2.55 (s, 3H), 1.20(d, 6H). HPLC-MS calculated C₂₉H₂₃ClN₆O₂ (M+1⁺): 523.2, found: 523.2.

Example 3525-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

To a suspension of 4-(3-Dimethylamino-acryloyl)-benzoic acid methylester (1 g, 4.29 mmol; Prepared according to the method reported by S.Murahashi et al. Bulletin of the Chemical Society of Japan, 1987, 60,3285) in MeOH (8.5 mL) is added guanidine hydrochloride (1.23 g, 12.86mmol) and NaOH (412 mg, 10.3 mmol). The mixture is stirred at 80° C. for24 h and then cooled down to room temperature. The mixture isconcentrated and treated with H₂SO₄/H₂O (1:1, 20 mL) and heated to 120°C. for 14 h. After cooling down to room temperature, the mixture isbasified by pouring into ice cold NH₄OH (50 mL) and acidified to pH=1 byadding concentrated hydrogen chloride solution. The precipitate iscollected by filtration, washed with acetonitrile and dried in a vacuumoven for 24 h to yield 680 mg of crude4-(2-hydroxy-pyrimidin-4-yl)-benzoic acid.

The crude 4-(2-hydroxy-pyrimidin-4-yl)-benzoic acid is treated withPOCl₃ (4 mL) at 100° C. for 14 h and cooled down to room temperature.POCl₃ is removed under vacuum and the residue is flushed once withtoluene (3 mL). The residue is dissolved in anhydrous dichloromethane (4mL) and put into ice bath. 4-Chloroaniline (790 mg, 6.28 mmol) is addedfollowed by the addition of Et₃N (1.2 g, 12 mmol). After stirring at 0°C. for 1 h, the mixture is poured into water (100 mL) and extracted withEtOAc (3×50 mL). The combined extracts is washed with brine, dried(MgSO₄) and concentrated. The residue is purified by flash columnchromatography (silica gel, 0˜80% EtOAc/hexane) to provide the desiredN-(4-chloro-phenyl)-4-(2-chloro-pyrimidin-4-yl)-benzamide as yellowsolid (650 mg, 44%). HPLC-MS calculated C₁₇H₁₁Cl₂N₃O (M+1⁺): 344.0,found: 344.0.

Step B:

5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared fromN-(4-chloro-phenyl)-4-(2-chloro-pyrimidin-4-yl)-benzamide and5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethylester by following a similar procedure as described in example 2. ¹H NMR(CDCl₃) δ (ppm) 8.68 (d, 1H), 8.15 (d, 2H), 8.01 (d, 2H), 7.63 (d, 1H),7.49 (m, 4H), 7.32 (m, 3H), 7.11 (d, 2H), 2.73 (s, 3H). HPLC-MScalculated C₂₈H₁₈Cl₂N₆OS (M+1⁺): 557.1, found: 557.1.

Example 3536-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

To a suspension of5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (10 mg,0.018 mmol) in propanol (0.5 mL) is added 4-methoxylbenzylamine (15 μL).The mixture is heated at 100° C. for 14 h and then cooled down to roomtemperature. Solvent is removed under vacuum, residue is used directlyfor next step without further purification.

Step B:

The residue from previous step is dissolved in TFA (0.5 mL) and heatedat 60° C. for 5 h. After cooling down to room temperature, the mixtureis concentrated and purified by preparative LC/MS to provide the titlecompound6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.¹H NMR (CDCl₃) δ (ppm) 8.23 (d, 1H), 8.12 (d, 2H), 8.01 (d, 2H), 7.52(m, 4H), 7.33 (m, 3H), 7.23 (d, 1H), 7.11 (d, 2H), 2.73 (s, 3H). HPLC-MScalculated C₂₈H₂₀ClN₇OS (M+1⁺): 538.1, found: 538.1.

Example 3555-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile

5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide (10 mg, 0.021 mmol; prepared from5-(4-chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid following the procedure as in example 342) is treated with POCl₃ at80° C. for 30 min. The mixture is then cooled down to room temperatureand concentrated under vacuum. The residue is treated with sat. aqueousNaHCO₃ solution (1 mL) and extracted with EtOAc. The combined extractsis then concentrated and purified by preparative thin layerchromatography (silica gel, 30% EtOAc/hexane) to provide the titlecompound5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrileas white solid. ¹H NMR (CDCl₃) δ (ppm) 8.13 (d, 2H), 7.54 (t, 2H), 7.44(t, 1H), 7.33 (d, 2H), 7.25 (d, 2H), 7.10 (m, 4H), 2.87 (m, 1H), 1.20(d, 6H). HPLC-MS calculated C₂₇H₂₀ClN₅O (M+1⁺): 466.1, found: 466.1.

Example 3565-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (230 mg,0.41 mmol) in CH₂Cl₂ (6 mL) is added m-CPBA (240 mg, 1.39 mmol) at 0° C.The mixture is stirred at 0° C. for 5 min and then allowed to warm up toroom temperature. After stirring at room temperature for 5 h, themixture is treated with saturated aqueous NaHCO₃ solution (10 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined extracts is washed withbrine, dried (MgSO₄) and concentrated. A small portion is purified bypreparative LC/MS to provide the title compound5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.¹H NMR (CDCl₃) δ (ppm) 8.69 (d, 1H), 8.09 (d, 2H), 8.03 (d, 2H), 7.64(d, 1H), 7.54 (t, 3H), 7.50 (d, 2H), 7.44 (t, 1H), 7.34 (d, 2H), 7.15(d, 1H), 3.53 (s, 3H). HPLC-MS calculated C₂₈H₁₈Cl₂N₆O₃S (M+1⁺): 589.1,found: 589.1. The rest of residue is used directly for Example 357.

Example 3576-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

To a suspension of crude5-(4-chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(from example 356) in EtOH (6 mL) is added 4-methoxylbenzylamine (0.4mL). The mixture is heated at 100° C. for 24 h and then cooled down toroom temperature. The precipitate is collected by filtration and washedwith EtOH (2×3 mL). The solid is air dried for 14 h to provide thedesired5-(4-chloro-phenyl)-3-methanesulfonyl-6-{4-[2-(4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid (230 mg, 80%). HPLC-MS calculated C₃₆H₂₈ClN₇O₄S (M+1⁺):690.2, found: 690.2.

Step B:

A solution of5-(4-chloro-phenyl)-3-methanesulfonyl-6-{4-[2-(4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(230 mg, 0.33 mmol) in TFA (4 mL) is stirred at 50° C. for 8 h and thencooled down to room temperature. The excess of TFA is removed undervacuum and the residue is treated with saturated aqueous NaHCO₃ solution(5 mL). After extracted with CH₂Cl₂, The combined extracts is washedwith brine, dried (MgSO₄) and concentrated. The residue is purified byflash column chromatography (silica gel, 0-2% MeOH/CH₂Cl₂) to providethe title compound6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.¹H NMR (CDCl₃) δ (ppm) 8.36 (d, 1H), 8.11 (d, 2H), 7.94 (d, 2H), 7.54(t, 2H), 7.45 (m, 3H), 7.34 (d, 2H), 7.15 (d, 2H), 7.03 (d, 1H), 5.34(b, 2H), 3.55 (s, 3H). HPLC-MS calculated C₂₈H₂₀ClN₇O₃S (M+1⁺): 570.1,found: 570.1.

Example 3616-[4-(2-Butoxy-ethyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of6-[4-(2-butoxy-vinyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(5 mg, 0.01 mmol) in EtOH (1 mL) is added Pd/C (2 mg). The system isdegassed by alternately applying vacuum and H₂ for 3 times. The mixtureis then stirred at room temperature under H₂ for 24 h. After removingthe catalyst by filtration, the filtrate is concentrated and purified byflash column chromatography (silica gel, 0-30% EtOAc/hexane) to providethe title compound as white solid (3.5 mg, 69%). HPLC-MS calculatedC₂₉H₂₅ClN₄O₂ (M+1⁺): 497.2, found: 497.2

Example 3625-(4-Chloro-phenyl)-6-[4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of5-(4-chloro-phenyl)-1-phenyl-6-[4-(1H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(4mg, 0.008 mmol) in MeCN (0.5 mL) is added K₂CO₃ (5 mg) followed by MeI(0.05 mL). The mixture is heated to 60° C. for 16 h and then cooled downto room temperature. The reaction mixture is then treated with water (3mL) and extracted with EtOAc. The combined extracts is concentrated andpurified by preparative thin layer chromatography (silica gel, 30%EtOA/hexane) to provide the title compound5-(4-chloro-phenyl)-6-[4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneas white solid (3.8 mg, 92%). ¹H NMR (CDCl₃) δ (ppm) 8.33 (s, 1H), 8.17(d, 2H), 7.70 (d, 2H), 7.51 (t, 2H), 7.38 (m, 4H), 7.11 (d, 2H), 6.54(d, 1H), 3.97 (s, 3H). HPLC-MS calculated C₂₇H₁₉ClN₆O (M+1⁺): 479.1,found: 479.1.

Example 3635-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Step A:

To a solution of 3,6-dichloro-pyridazine (500 mg, 3.36 mmol) in EtOH (6mL) is added hydrazine hydrate (840 mg, 16.8 mml) The mixture is heatedat 80° C. for 14 h and then cooled downed to room temperature. Thesolvent is removed under vacuum and the residue is triturated with water(2 mL), filtered off and dried to afford6-chloro-3-pyridazinyl-hydrazine (280 mg, 58%) as white solid. HPLC-MScalculated C₄H₅ClN₄ (M+1⁺): 145.0, found: 145.0.

Step B:

To a vigorously stirred suspension of yellow mercuric oxide (840 mg,3.88 mmol) in water (10 mL) is slowly added6-chloro-3pyridazinyl-hydrazine (280 mg, 1.94 mmol) portion wise. Theresulted mixture is then stirred at room temperature for 5 h andextracted with EtOAc (3×15 mL). The combined extracts is washed withbrine, dried (MgSO₄) and concentrated to provide the desired product3-chloropyridazine as brownish solid (130 mg, 34%). HPLC-MS calculatedC₄H₃ClN₂ (M+1⁺): 115.0, found: 115.0.

Step C:

5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared from 3-chloropyridazine and5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneby using the same method described in example 338. The crude product ispurified by flash column chromatography (silica gel, 0˜70%EtOAc/hexane). ¹H NMR (CDCl₃) δ (ppm) 9.19 (b, 1H), 8.34 (s, 1H), 8.15(d, 2H), 8.02 (d, 2H), 7.84 (d, 1H), 7.51 (m, 5H), 7.33 (m, 3H), 7.15(d, 2H). HPLC-MS calculated C₂₇H₁₇ClN₆O (M+1⁺): 477.1, found: 477.1.

Example 3715-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneis prepared from5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-oneand 2-chloro-pyrazine by using the method described in example 338except that the reaction mixture is stirred at 100° C. for 14 hours: ¹HNMR (CDCl₃) δ (ppm) 9.02 (d, 1H), 8.67 (t, 1H), 8.55 (d, 1H), 8.35 (s,1H), 8.15 (d, 2H), 7.95 (d, 2H), 7.51 (m, 4H), 7.37 (t, 1H), 7.33 (d,2H), 7.14 (d, 2H). HPLC-MS calculated C₂₇H₁₇ClN₆O (M+1⁺): 477.1, found:477.1.

Example 3775-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one

Step A:

To a freshly prepared NaOEt (1.18 mmol) solution in EtOH (0.75 mL) isadded ethyl cyanoacetate (100 mg, 0.88 mmol) at 0° C. After stirring at0° C. for 10 min., azido-benzene (100 mg, 0.84 mmol, prepared accordingto the method reported by M. Kurumi et al. Heterocycles. 2000, 53, 2809)is added. After the addition, the mixture is allowed to slowly warm upto room temperature and stirred for 14 h. The mixture is then treatedwith water (3 mL) and extracted with EtOAc (3×3 mL). The combinedextracts is concentrated and purified by flash column chromatography(silica gel, 0%˜70% EtOAc/hexane) to provide5-amino-1-phenyl-1H-[1,2,3-]triazole-4-carboxylic acid ethyl ester as awhite solid (100 mg, 51%). HPLC-MS calculated C₁₁H₁₂N₄O₂ (M+1⁺): 233.1,found: 233.1.

Step B:

A mixture of 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethylester (30 mg, 0.13 mmol), 4-bromo-N-(4-chloro-phenyl)-benzimidoylchloride (51 mg, 0.16 mmol) and TiCl₄ (20 μL) in anhydrousdichloroethane (1 mL) is heated in microwave reactor at 170° C. for 1 hand then at 115° C. for 48 h in an oil bath. After cooling down to roomtemperature, the mixture is worked up as in example 2 and purified byflash column chromatography (silica gel, 0˜30% EtOAc/hexane) to providethe title compound5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-oneas white solid. (45 mg, 73%). ¹H NMR (CDCl₃) δ (ppm) 8.15 (d, 2H), 7.59(t, 2H), 7.49 (t, 1H), 7.43 (d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 7.10(d, 2H), 2.87 (m, 1H). HPLC-MS calculated C₂₂H₁₃BrClN₅O (M+1⁺): 478.0,found: 478.0.

Example 3833-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamide

Step A:

A solution of3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester (200 mg, 0.37 mmol) in THF/MeOH/H₂O 3:2:1 (5 mL) wascooled to 0° C. and treated with 3 N aqueous LiOH (183 μL, 0.55 mmol).The reaction mixture was allowed to warm to room temperature and wasstirred for 4 h. The reaction was diluted with H₂O, extracted with Et₂O,and acidified with 1 N aqueous HCl. The resulting white precipitate wascollected by suction filtration to provide3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid (155 mg, 82%) as a white solid. HPLC-MS calculated for C₃₀H₁₉ClN₄O₃(M+H⁺): 519.1, found 519.1.

Step B:

A solution of3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid (40 mg, 0.077 mmol) in SOCl₂ (1 mL) was heated at 70° C. for 1 h.The reaction mixture was allowed to cool to room temperature and pouredinto a 50% aqueous solution of NH₄OH (15 mL). The resulting mixture wasdiluted with H₂O and extracted with CH₂Cl₂. The combined organics weredried (MgSO₄), filtered, and concentrated. The crude material waspurified by flash column chromatography (silica gel, 5% MeOH/CH₂Cl₂) togive the title compound3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamideas a white solid. ¹H NMR (CDCl₃) δ (ppm) 8.67 (s, 1H), 8.29 (t, 1H),8.15 (br s, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.71 (t, 1H), 7.64 (d, 2H),7.58 (d, 3H), 7.46 (br s, 2H), 7.44 (m, 6H), 7.37 (m, 1H); HPLC-MScalculated for C₃₀H₂₀ClN₅O₂ (M+H⁺): 518.1, found 518.1.

Example 384N-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-methanesulfonamide

Step A:

A solution of2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one(51 mg, 0.104 mmol) in CCl₄ (2 mL) was treated sequentially with NBS (24mg, 0.135 mmol) followed by AIBN (22 mg, 0.135 mmol). The reaction washeated at 80° C. for 3 h, allowed to cool to room temperature, andconcentrated in vacuo. The crude oil was purified by flash columnchromatography (silica, 0-30% Hex/EtOAc) to provide2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(46 mg, 78%) as a white solid. HPLC-MS calculated for C₃₀H₂₀BrClN₄O(M+H⁺): 567.1, found 567.1.

Step B:

A solution of N-(4-methoxy-benzyl)-methanesulfonamide (7.8 mg, 0.035mmol) in anhydrous DMF (0.3 mL) was treated with 60% dispersed NaH (1.4mg, 0.059 mmol). The reaction mixture was stirred until the evolution ofhydrogen ceased and added via syringe to a solution of2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(20 mg, 0.35 mmol) in anhydrous DMF (0.1 mL). The resulting reactionmixture was heated at 50° C. for 2 h, allowed to cool to roomtemperature, and quenched with 1 N aqueous HCl. The resulting whiteprecipitate was collected by suction filtration to provideN-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-N-(4-methoxy-benzyl)-methanesulfonamide(18 mg, 72%) as a white solid. HPLC-MS calculated for C₃₉H₃₂BrClN₅O₄S(M+H⁺): 702.2, found 702.2.

Step C:

A solution ofN-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-N-(4-methoxy-benzyl)-methanesulfonamide(18 mg, 0.026 mmol) in TFA (1 mL) was heated at 90° C. in a sealed tubefor 12 h. The reaction mixture was concentrated in vacuo and theresulting crude oil was purified by flash chromatography (silica, 5%MeOH/CH₂Cl₂) to give the title compoundN-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-methanesulfonamideas a white solid. ¹H NMR (CDCl₃) δ (ppm) 7.64-7.54 (m, 3H), 7.51-7.45(m, 4H), 7.44-7.38 (m, 4H), 7.37-7.30 (m, 4H), 7.28 (s, 1H), 7.13 (d,2H), 5.92 (br s, 1H), 4.48 (s, 2H), 2.99 (s, 3H); HPLC-MS calculated forC₃₁H₂₄ClN₅O₃S (M+H⁺): 582.1, found 582.1.

Example 3862-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-methanesulfonylmethyl-9-phenyl-1,9-dihydro-purin-

Step A:

A solution of2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(17 mg, 0.030 mmol) in anhydrous DMF (0.2 mL) was treated with sodiumthiomethoxide (3 mg, 0.042 mmol). The reaction mixture was stirred for10 min and acidified with 1 N aqueous HCl. The resulting precipitate wascollected by filtration to give2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methylsulfanylmethyl-9-phenyl-1,9-dihydro-purin-6-one(14 mg, 86%) as a white solid. HPLC-MS calculated for C₃₁H₂₃ClN₄OS(M+H⁺): 535.1, found 535.1.

Step B:

A solution of2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methylsulfanylmethyl-9-phenyl-1,9-dihydro-purin-6-one(14 mg, 0.026 mmol) in CH₂Cl₂ (0.5 mL) was treated with MCPBA (9 mg,0.052 mmol). The reaction mixture was gently heated at 40° C. for 2hours, allowed to cool to room temperature, and concentrated in vacuo.The crude amorphous solid was purified by flash chromatography (silica,0-20% EtOAc/CH₂Cl₂) to provide the title compound2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methanesulfonylmethyl-9-phenyl-1,9-dihydro-purin-6-oneas a white solid. ¹H NMR (CDCl₃ δ (ppm) 7.65-7.53 (m, 5H), 7.49 (d, 2H),7.41-7.39 (m, 4H), 7.37-7.31 (m, 3H), 7.29-7.24 (m, 2H, partiallyobscured by CHCl₃), 7.16 (d, 2H), 4.43 (br s, 2H), 3.35 (br s, 3H);HPLC-MS calculated for C₃₁H₂₃ClN₄O₃S (M+H⁺): 567.1, found 567.1.

Example 3913-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamide

A solution of3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid (50 mg, 0.096 mmol) in SOCl₂ (1 mL) was heated at 70° C. for 1 h.The reaction mixture was concentrated, dissolved in CH₂Cl₂ (2 mL), andtreated with 3-aminoisoxazole (2.97 mg, 0.035 mmol). The reactionmixture was stirred at room temperature for 1 h, concentrated, andpurified by flash column chromatography (silica gel, 0-30% Hex/EtOAc) togive the title compound3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamideas a white solid. ¹H NMR (CDCl₃ (ppm) 9.94 (s, 1H), 8.46 (s, 1H), 8.32(s, 1H), 8.29 (s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.72 (t, 1H), 7.49(d, 2H), 7.45 (d, 2H), 7.39 (t, 2H), 7.35-7.29 (m, 5H), 7.25 (br s, 1H),7.14 (d, 2H); HPLC-MS calculated for C₃₀H₂₀ClN₅O₂ (M+H⁺): 585.1, found585.1.

Example 4472-[4-(6-Amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one

Step A:

A solution of2-(4-Bromo-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(190 mg, 0.40 mmol) in anhydrous DMF (3.5 mL) was treated sequentiallywith bis(pinacolato)diboron (108 mg, 0.46 mmol), KOAc (117 mg, 1.19mmol), and Pd(dppf)₂Cl₂ (16 mg, 0.02 mmol). The resulting suspension wasdegassed with N₂ and heated at 100° C. for 2 h. The reaction mixture wasallowed to cool to room temperature, diluted with H₂O, and extractedwith EtOAc. The combined organics were dried (MgSO₄), filtered, andconcentrated. The crude material was purified by flash columnchromatography (silica, 0-20% EtOAc/CH₂Cl₂) to give1-(4-chloro-phenyl)-9-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one(180 mg, 86%) as a light tan solid. HPLC-MS calculated for C₂₉H₂₆ClN₄O₃(M+H⁺): 525.2, found 525.2.

Step B:

A solution of1-(4-chloro-phenyl)-9-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,9-dihydro-purin-6-one(180 mg, 0.34 mmol) and 2-amino-5-bromopyridine (89 mg, 0.51 mmol) inanhydrous DMF (3 mL) was treated sequentially with Cs₂CO₃ (224 mg, 0.69mmol) and Pd(dppf)₂Cl₂ (14 mg, 0.017 mmol). The reaction mixture wasdegassed with N₂ and heated at 100° C. for 24 h. The reaction was cooledto room temperature, diluted with H₂O, and extracted with EtOAc. Thecombined organics were dried (MgSO₄), filtered, and concentrated. Thecrude material was purified by flash column chromatography (silica, 30%EtOAc/CH₂Cl₂) to provide the title compound2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-oneas a white solid. ¹H NMR (CDCl₃) δ (ppm) 8.19 (s, 1H), 7.95 (m, 2H),7.72 (d, 2H), 7.61 (apparent t, 2H), 7.52 (apparent t, 1H), 7.42 (d,2H), 7.35 (m, 4H), 7.17 (d, 2H), 6.95 (d, 1H); HPLC-MS calculated forC₂₈H₁₉ClN₆O (M+H⁺): 491.1, found 491.1.

Example 4481-(4-Chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one

A solution of2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one(10 mg, 0.02 mmol) in acetonitrile (0.4 mL) and H₂O (0.4 mL) was treatedwith NaNO₂ and 5 μL of concentrated H₂SO₄. The reaction mixture washeated at 100° C. for 1 h. The reaction was allowed to cool to roomtemperature and neutralized with aqueous Na₂CO₃. The reaction wasdiluted with H₂O and extracted with EtOAc. The combined organics weredried (MgSO₄), filtered, and concentrated. The resulting crude materialwas purified by preparative LCMS to provide the title compound1-(4-chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one_asa white solid. ¹H NMR (CDCl₃) δ (ppm) 8.21 (s, 1H), 8.01 (dd, 1H), 7.81(d, 1H), 7.58 (apparent t, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 7.33 (m,3H), 7.14 (d, 2H), 6.98 (d, 1H); HPLC-MS calculated for C₂₈H₁₈ClN₅O₂(M+H⁺): 492.1, found 492.1.

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1, are obtained.

TABLE 1 Physical Data Compound ¹H NMR 400 MHz (CDCl₃) Number Structureand/or MS (m/z) 10

The title compound is prepared as described in Example 2, using 4-fluorobenzoyl chloride instead of p-toluoyl chloride. ¹H NMR (CDCl₃, 400MHz) δ 8.33 (s, 1H), 8.12 (d, 2H), 7.50 (m, 4H), 7.35 (m, 3H), 7.02 (d,2H), 6.96 (t, 2H); HPLC-MS calculated for C₂₃H₁₄BrFN₄O (M + H⁺) 461.0,found 461.1. 11

LCMS: 458.0 (M + H⁺). 12

LCMS: 429.0 (M + H⁺). 13

The title compound is prepared as described in Example 1. ¹H NMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 8.05 (d, J = 7.51 Hz, 2H), 7.48-7.38 (m, 3H),7.32-7.26 (m, 4H), 7.2-7.17 (m, 1H), 7.05 (t, J = 7.57 Hz, 1H), 6.88 (t,J = 9.3 Hz, 1H). LC/MS found: 451.1 (M + H⁺). 14

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 8.01 (d, J = 7.62 Hz, 2H), 7.44-7.37 (m, 4H),7.3 (d, J = 7.41 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.19-7.07 (m, 3H),6.9 (d, J = 7.6 Hz, 1H). LC/MS found: 511.0 (M + H⁺). 15

The title compound is prepared as described in Example 1. ¹H NMR (CDCl₃,400 MHz) δ 8.27 (s, 1H), 8.0 (d, J = 7.62 Hz, 2H), 7.43- 7.39 (m, 2H),7.31-7.2 (m, 3H), 7.12-7.05 (m. 2H), 7.02- 6.92 (m, 3H). LC/MS found:451.0 (M + H⁺). 16

The title compound is prepared as described in Example 1. ¹H NMR (CDCl₃,400 MHz) δ 8.35 (s, 1H), 8.14 (d, J = 7.6 Hz, 2H), 7.53-7.5 (m, 2H),7.45 (d, J = 2.2 Hz, 1H), 7.41-7.33 (m, 3H), 7.3- 6.26 (m, 3H), 7.19 (d,J = 8.45 Hz, 1H). LC/MS found: 467.1 (M + H⁺). 17

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.31 (s, 1H), 8.09 (d, J = 7.4 Hz, 2H), 7.51-7.47 (m, 2H),7.37-7.26 (m, 5H), 7.15-7.06 (m, 3H). LC/MS found: 451.1 (M + 1/z). 18

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.34 (s, 1H), 8.12 (d, J = 7.7 Hz, 2H), 7.51-7.49 (m, 2H),7.41-7.28 (m, 5H), 7.19-7.12 (m, 1H), 6.94-6.84 (m, 1H). LC/MS found:435.0 (M + 1/z). 19

The title compound is prepared as described in Example 1. ¹H NMR (CDCl3,400 MHz) δ 8.32 (s, 1H), 8.07 (d, J = 8.05 Hz, 2H), 7.46 (t, J = 7.9 Hz,2H), 7.4 (d, J = 8.55 Hz, 2H), 7.34-7.32 (m, 2H), 7.24 (s, 1H), 7.1 (t,J = 7.5 Hz, 1H), 7.01 (t, J = 7.15 Hz, 2H), 6.88 (t, J = 9 Hz, 1H).LC/MS found: 461.0 (M + 1/z). 20

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.32 (s, 1H), 8.12 (d, J = 7.6 Hz, 2H), 7.53-7.49 (m, 2H),7.38-7.33 (m, 3H), 7.29-7.23 (m, 5H), 7.1-7.05 (m, 3H), 7.08 (d. J = 8.7Hz. 2H). LC/MS found: 433.1 (M + 1/z). 21

The title compound is prepared as described in Example 1. ¹HNMR (CDCl3,400 MHz) δ 8.37 (s, 1H), 8.12 (d, J = 7.6 Hz, 2H), 7.53-7.49 (m, 2H),7.38-7.31 (m, 3H), 7.16-7.1 (m, 3H), 7.02-6.98 (m, 2H), 6.94-6.89 (m,1H). LC/MS found: 401.1 (M + 1/z). 22

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.32 (s, 1H), 8.13 (d. J = 7.6 Hz, 2H), 7.53-7.49 (m, 2H),7.36-7.31 (m, 1H), 7.38-7.34 (m, 1H). 7.28-7.23 (m, 5H), 7.14-7.04 (m,4H). LC/MS found: 417.1 (M + 1/z). 23

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.46-7.42 (m, 2H),7.32-7.26 (m, 3H), 7.23-7.2 (m, 2H), 7.1-7.05 (m, 3H), 6.88-6.83 (m,1H). LC/MS found: 417.1 (M + 1/z). 24

The title compound is prepared as described in Example 2, using 2-chlorobenzoyl chloride instead of p-toluoyl chloride. HPLC-MS calculatedfor C₂₃H₁₄BrClN₄O (M + H⁺) 477.0. found 477.0. 25

The title compound is prepared as described in Example 2, using 3-chlorobenzoyl chloride instead of p-toluoyl chloride. HPLC-MS calculatedfor C₂₃H₁₄BrClN₄O (M + H⁺) 477.0, found 477.0. 26

The title compound is prepared as described in Example 2, using 2-bromobenzoyl chloride instead of p-toluoyl chloride. HPLC-MS calculatedfor C₂₃H₁₄BrN₄O (M + H+ ) 521.0, found 520.9. 27

The title compound is prepared as described in Example 2, using 2,4-difluorobenzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₃H₁₃BrF₂N₄O (M + H⁺) 479.0, found 479.1. 28

The title compound is prepared as described in Example 2, using 4-biphenylcarbonyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₉H₁₉BrN₄O (M + H⁺) 519.1, found 519.1. 29

The title compound is prepared as described in Example 2, using 3,4-dichlorobenzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₃H₁₃BrCl₂N₄O (M + H⁺) 511.0, found 511.0. 30

The title compound is prepared as described in Example 2, usingcommercially available 4- chlorobenzanilide instead of preparing it fromaniline and 4-chlorobenzoyl chloride. ¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s,1H), 8.13 (d, 2H), 7.51 (t, 2H), 7.36 (m, 4H), 7.28 (d, 2H), 7.20 (d,2H), 7.14 (dd, 2H); HPLC-MS calculated for C₂₃H₁₅ClN₄O (M + H⁺) 399.1,found 399.1. 31

5-Amino-1-pyridin-2-yl-1H- pyrazole-4-carboxylic acid ethyl ester isprepared as described in Reference 1. The title compound is prepared asdescribed in Example 2, using 2- fluorobenzoyl chloride instead ofp-toluoyl chloride and 5- amino-1-pyridin-2-yl-1H- pyrazole-4-carboxylicacid ethyl ester instead of ethyl 5- amino-1-phenyl-4-pyrazole-carboxylate. HPLC-MS calculated for C₂₂H₁₃BrFN₅O (M + H⁺) 462.0, found462.0. 32

The title compound is prepared as described in Example 2, usingo-toluoyl chloride instead of p-toluoyl chloride. HPLC-MS calculated forC₂₄H₁₇BrN₄O (M + H⁺) 457.1, found 457.0. 33

The title compound is prepared as described in Example 2, using 3-fluorobenzoyl chloride instead of p-toluoyl chloride. ¹H NMR (CDCl₃, 400MHz) δ 8.34 (s, 1H), 8.11 (d, 2H), 7.52 (t, 2H), 7.49 (d, 2H), 7.37 (t,1H), 7.22 (m, 1H), 7.11 (d, 1H), 7.03 (m, 4H); HPLC-MS calculated forC₂₃H₁₄BrFN₄O (M + H⁺) 1461.0, found 461.0. 34

5-Amino-1-cyclohexyl-1H- pyrazole-4-carboxylic acid ethyl ester isprepared as described in Reference 1. The title compound is prepared asdescribed in Example 2, using 2- fluorobenzoyl chloride instead ofp-toluoyl chloride and 5- amino-1-cyclohexyl-1H- pyrazole-4-carboxylicacid ethyl ester instead of ethyl 5- amino-1-phenyl-4-pyrazole-carboxylate. HPLC-MS calculated for C₂₃H₂₀BrFN₄O (M + H⁺) 467.1, found467.0. 35

The title compound is prepared as described in Example 2, using benzoylchloride instead of p-toluoyl chloride. HPLC-MS calculated forC₂₃H₁₅BrN₄O (M + H⁺) 443.0, found 443.1. 36

The title compound is prepared as described in Example 2, usingm-toluoyl chloride instead of p-toluoyl chloride. HPLC-MS calculated forC₂₄H₁₇BrN₄O (M + H⁺) 457.1, found 457.0. 37

The title compound is prepared as described in Example 1. ¹HNMR (CDCl₃,400 MHz) δ 8.29 (s, 1H), 8.10 (d, J = 7.5 Hz, 2H), 7.5-7.45 (m, 4H),7.36-7.31 (m, 1H), 7.26-7.2 (m, 5H), 6.99 (d, J = 8.66 Hz, 2H). LC/MSfound: 477.1 (M + 1/z). 38

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.39 (d, 2H), 7.26-7.33 (m, 2H),7.11 (t, 1H), 7.01 (bd, 2H), 6.90 (t, 1H), 1.80 (s, 9H); HPLC-MScalculated for C₂₁H₁₈BrFN₄O (M + H⁺): 440.1, found 440.2. 39

¹H NMR (CDCl₃) δ (ppm) 8.32 (s, 1H), 7.95 (d, 2H), 7.41 (d, 2H),7.28-7.35 (m, 2H), 7.11 (t, 1H), 7.03 (bd, 2H), 7.00 (d, 2H), 6.90 (t,1H); HPLC-MS calculated for C₂₄H₁₆BrFN₄O₂ (M + H⁺): 491.0, found 491.2.40

5-(4-chloro-phenyl)-6-(2,4- dichloro-phenyl)-4-methoxy-1-phenyl-1H-pyrazolo[3,4- b]pyridine is prepared in 78% yield asdescribed in Example 4 except using MeOH as solvent. ¹H NMR (CDCl₃) δ(ppm) 8.44 (s, 1H), 8.30 (d, 2H), 7.49 (t, 2H), 7.24- 7.33 (m, 2H), 7.20(d, 2H), 7.04-7.15 (m, 4H), 4.36 (s, 3H); HPLC-MS calculated forC₂₅H₁₆C₁₃N₃O (M + H⁺): 480.0, found 480.2. 41

LCMS: 479.0 (M + H)⁺. 42

¹HNMR (CDCl₃): δ 8.25 (2 H, d, J = 8.8 Hz), 8.20 (1H, s), 7.60 (2H, dd,J = 2.0, 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.15-7.22 (2 H, m), 6.99(1H, t, J = 8..8 Hz), 6.86 (2 H, d, J = 6.8 Hz), 6.78 (1H, t, J = 8.8Hz) ppm; LCMS: 486.0 (M + H)⁺. 43

¹HNMR (CDCl₃): δ 8.46 (1H, s), 8.02 (1H, d, J = 8.8 Hz), 7.98 (1 H,brs), 7.55 (2H, d, J = 8.8 Hz), 7.45-7.49 (3H, m), 7.37 (1H, d, J = 6.8Hz), 7.30 (1H, dt, J = 2.0, 6.8), 7.18 (2H, d, J = 8.8), 7.03 (1H, dt, J= 2.0, 6.8), 2.56 (3H, s) ppm; LCMS: 475.0 (M + H)⁺. 44

¹HNMR (CDCl₃): δ 8.22 (1H, s), 8.20 (2H, d, J = 8.8 Hz), 7.60 (1H, d, J= 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.19-2.26 (2 H, m), 7.10 (1H, dt, J= 0.8, 6.8 Hz), 6.89 (2 H, d, J = 6.8 Hz), 6.80 (1H, dt, J = 0.8, 6.8Hz) ppm. 45

The title compound is prepared as described in Example 2, usingp-anisoyl chloride instead of p-toluoyl chloride. ¹H NMR (CDCl₃, 400MHz) δ 8.30 (s, 1H), 8.16 (d, 2H), 7.50 (m, 4H), 7.35 (t, 1H), 7.28 (d,2H), 7.03 (d, 2H), 6.76 (d, 2H), 3.79 (s, 3H); HPLC-MS calculated forC₂₄H₁₇BrN₄O₂ (M + H⁺) 473.0, found 473.0. 46

The title compound is prepared as described in Example 2, using 4-trifluoromethoxy-benzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₄H₁₄BrF₃N₄O₂ (M + H⁺) 527.0, found 527.0. 47

The title compound is prepared as described in Example 2, using4-tert-butyl- benzoyl chloride instead of p- toluoyl chloride. HPLC-MScalculated for C₂₇H₂₃BrN₄O (M + H⁺) 499.1, found 499.1. 48

The title compound is prepared as described in Example 2, using 2-trifluoromethyl-benzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₄H₁₄BrF₃N₄O (M + H⁺) 511.0, found 511.0. 49

The title compound is prepared as described in Example 2, using 2,6-difluoro-benzoyl chloride instead of p-toluoyl chloride. ¹H NMR (CDCl₃,400 MHz) δ 8.35 (s, 1H), 8.07 (d, 2H), 7.49 (t, 2H), 7.45 (d, 2H), 7.35(t, 1H), 7.30 (t, 1H), 7.12 (d, 2H), 6.81 (t, 2H); HPLC- MS calculatedfor C₂₃H₁₃BrF₂N₄O (M + H⁺) 479.0, found 479.0. 50

The title compound is prepared as described in Example 2, using 2,6-dichloro-benzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₃H₁₃BrCl₂N₄O (M + H⁺) 511.0, found 511.0. 51

The title compound is prepared as described in Example 2, using 2,4,6-trifluoro-benzoyl chloride instead of p-toluoyl chloride. HPLC-MScalculated for C₂₃H₁₂BrF₃N₄O (M + H⁺) 497.0, found 497.0. 52

The title compound is prepared as described in Example 2, usingo-anisoyl chloride instead of p-toluoyl chloride. ¹H NMR (CDCl₃, 400MHz) δ 8.32 (s, 1H), 8.13 (dd, 2H), 7.47 (m, 3H), 7.32 (m, 5H), 6.95(td, 1H), 6.71 (br, 1H), 6.63 (d, 1H), 3.60 (s, 3H); HPLC-MS calculatedfor C₂₄H₁₇BrN₄O₂ (M + H⁺) 473.0, found 473.0. 53

The title compound is prepared as described in Example 2, using 4-trifluoromethyl-benzoyl chloride instead of p-toluoyl chloride. ¹HNMR(CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.11 (dd, 2H), 7.50 (m, 8H), 7.37 (t,1H), 7.03 (d, 2H); HPLC- MS calculated for C₂₄H₁₄BrF₃N₄O (M + H⁺) 511.0,found 511.0. 54

The title compound is prepared as described in Example 2, using 4-biphenylcarbonyl chloride instead of p-toluoyl chloride and4-chloroaniline instead of 4-bromoaniline. ¹H NMR (CDCl₃, 400 MHz) δ8.33 (s, 1H), 8.17 (d, 2H), 7.56-7.33 (m, 14H), 7.13 (d, 2H); HPLC-MScalculated for C₂₉H₁₉ClN₄O (M + H⁺) 475.1, found 475.1. 55

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.67 (d, 2H), 7.54 (t, 2H), 7.43(m, 3H), 7.27 (m, 2H), 7.07 (m, 3H), 6.88 (t, 1H); HPLC-MS calculatedfor C₂₃H₁₄BrFN₄O (M + H⁺): 461.0, found 461.0. 56

HPLC-MS calculated for C₂₄H₁₄FN₅O (M + 1⁺): 408.1, found: 408.2 57

HPLC-MS calculated for C₂₄H₁₇FN₄O; (M + 1⁺): 413.3, found: 413.3 58

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.11 (d, 2H), 7.49 (t, 2H),7.26-7.33 (m, 3H), 7.05-7.15 (m, 5H), 6.90 (t, 1H), 4.43 (s, 3H);HPLC-MS calculated for C₂₄H₁₇FN₄OS (M + 1⁺): 429.1, found: 429.2. 59

HPLC-MS calculated for C₂₇H₂₃FN₄O (M + 1⁺): 439.2, found: 439.2. 60

HPLC-MS calculated for C₂₅H₁₇FN₄O₃ (M + 1⁺): 441.1, found: 441.2. 61

HPLC-MS calculated for C₂₇H₂₃FN₄O₂ (M + 1⁺): 455.2, found: 455.2 62

HPLC-MS calculated for C₂₉H₁₉FN₄O (M + 1⁺): 459.2; found: 459.2. 63

HPLC-MS calculated for C₂₄H₁₄F₄N₄O₂ (M + 1⁺): 467.1, found: 467.2 64

¹H NMR (CDCl₃) δ (ppm) 8.36 (s, 1H), 8.10 (d, 2H), 7.56 (d, 2H), 7.50(t, 2H), 7.26- 7.37 (m,5H), 7.12 (t, 1H), 6.88 (t, 1H); HPLC-MScalculated for C₂₄H₁₄F₄N₄O (M + 1⁺): 451.1, found: 451.1. 65

¹HNMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.05 (d, 2H), 7.42-7.52 (m, 3H),7.31 (t, 1H), 7.05-7.25 (m, 6H), 6.83 (d, 2H), 5.70 (bd, 1H), 4.85 (bd,1H); HPLC-MS calculated for C₂₄H₁₇FN₄O (M + 1⁺): 397.1, found: 397.2. 66

HPLC-MS calculated for C₂₃H₂₁FN₄O (M + 1⁺): 389.2, found: 389.2. 67

¹H NMR (CDCl₃) δ (ppm) 8.15 (s, 1H), 7.39 (d, 2H), 7.29-7.35 (m, 2H),7.12 (t, 1H), 7.00 (bd, 2H), 6.90 (t, 1H), 4.05 (s, 3H); HPLC-MScalculated for C₁₈H₁₂BrFN₄O (M + 1⁺): 399.0, found: 399.1. 70

HPLC-MS calculated for C₂₅H₁₇C₁₂N₃O (M + 1⁺): 446.1, found: 446.2. 71

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.12 (d, 2H), 7.48 (t, 2H),7.26-7.353 (m, 3H), 7.03-7.10 (m, 5H), 6.88 (t, 1H), 2.28 (s, 3H);HPLC-MS calculated for C₂₄H₁₇FN₄O (M + 1⁺): 397.1, found: 397.2. 72

¹H NMR (CDCl₃) δ (ppm) 8.19 (s, 1H), 7.61 (d, 2H), 7.46 (t, 1H), 7.29(m, 2H), 7.26 (d, 1H), 7.19 (d, 2H), 7.06 (d, 2H), 6.72 (dd, 1H), 5.92(d, 1H); HPLC-MS calculated for C₂₄H₁₅Cl₃N₄ (M + H⁺): 465.0, found465.0. 73

¹H NMR (CDCl₃) δ (ppm) 8.07 (s, 1H), 7.51 (d, 2H), 7.44 (d, 2H), 7.32 (d2H), 7.29 (d, 1H), 7.21 (b, 1H), 7.13 (m, 2H), 6.98 (b, 1H), 2.41 (s,3H); HPLC-MS calculated for C₂₄H₁₅BrCl₂N₄O (M + H⁺): 525.0, found 525.0.75

¹H NMR (CDCl₃) δ (ppm) 8.13 (s, 1H), 7.67 (d, 2H), 7.56 (t, 3H), 7.48(m, 3H), 7.21 (m, 3H), 7.03 (d, 2H); HPLC-MS calculated forC₂₃H₁₄BrClN₄O (M + H⁺): 477.0, found 477.0 76

¹H NMR (CDCl₃) δ (ppm) 8.16 (s, 1H), 7.67 (d, 2H), 7.59 (t, 2H), 7.50(m, 4H), 7.27 (s, 1H), 7.03 (m, 3H); HPLC-MS calculated forC₂₃H₁₃BrC₁₂N₄O (M + H⁺): 511.0, found 511.0. 77

¹H NMR (CDCl₃) δ (ppm) 8.12 (s, 1H), 7.70 (d, 2H), 7.55 (t, 2H), 7.45(m, 3H), 7.15 (d, 2H), 7.03 (m, 4H); HPLC-MS calculated for C₂₄H₁₇BrN₄O(M + H⁺): 457.0, found 457.0. 78

¹H NMR (CDCl₃) δ (ppm) 8.16 (s, 1H), 7.67 (d, 2H), 7.57 (t, 2H), 7.49(m, 5H), 7.41 (d, 2H), 7.04 (d, 2H); HPLC-MS calculated forC₂₄H₁₄BrF₃N₄O (M + H⁺): 511.0, found 511.0. 80

¹H NMR (CDCl₃) δ (ppm) 8.51 (s, 1H), 8.34 (d, 2H), 7.56 (t, 2H), 7.46(d, 2H), 7.32~7.43 (m, 7H); HPLC- MS calculated for C₂₃H₁₄Cl₂N₄ (M +H⁺): 417.1, found: 417.1. 81

¹H NMR (CDCl₃) δ (ppm) 8.37 (s, 1H), 8.29 (d, 2H), 7.49 (t, 2H),7.26-7.34 (m, 2H), 7.22 (d, 2H), 7.07-7.13 (m, 4H), 4.69 (t, 2H), 3.90(t, 2H); HPLC-MS calculated for C₂₆H₁₈Cl₃N₃O₂ (M + H⁺): 510.1, found:510.1. 82

HPLC-MS calculated for C₂₂H₁₈BrFN₄OS (M + H⁺): 485.0, found: 485.0. 83

¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.32 (d, 2H), 7.47 (t, 2H), 7.27(t, 1H), 7.23 (d, 2H), 7.16 (d, 2H), 7.11 (d, 2H), 7.03 (d, 2H), 2.91(s, 6H); HPLC-MS calculated for C₂₆H₂₀Cl₂N₄ (M + H⁺): 459.1, found:459.1. 84

¹H NMR (CDCl₃) δ (ppm) 8.18 (s, 1H), 7.40 (d, 2H), 7.34 (qd, 1H), 7.28(d, 1H), 7.12 (t, 1H), 7.00 (bd, 2H), 6.92 (t, 1H), 5.07 (m, 1H), 3.58(td, 2H), 3.13 (td, 2H), 2.75~2.82(m, 2H), 2.53~2.59(m, 2H); HPLC-MScalculated for C₂₂H₁₈BrFN₄O₃S (M + H⁺): 517.0, found: 517.0. 85

¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.12 (d, 2H), 8.01 (d, 2H),7.48-7.54 (m, 4H), 7.37 (t, 1H), 7.32 (d, 2H), 7.10 (d, 2H), 2.47 (s,3H); HPLC-MS calculated for C₂₆H₁₇ClN₆O₂ (M + H⁺): 481.1, found: 481.1.86

HPLC-MS calculated for C₂₆H₁₆ClN₅O₂ (M + H⁺): 466.1, found: 466.1. 87

HPLC-MS calculated for C₂₆H₁₇ClN₆O (M + H⁺): 465.1, found: 465.1. 88

HPLC-MS calculated for C₂₅H₁₇ClN₄O₂ (M + H⁺): 441.1, found: 441.1. 89

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.12 (d, 2H), 7.70 (d, 2H), 7.51(t, 2H), 7.43 (d, 2H), 7.36 (t, 1H), 7.32 (d, 2H), 7.09 (d, 2H), 5.99(b, 1H), 5.63 (b, 1H); HPLC-MS calculated for C₂₄H₁₆ClN₅O₂ (M + H⁺):442.1, found: 442.1. 90

¹H NMR (CDCl₃) δ (ppm) 8.35 (b, 1H), 8.34 (s, 1H), 8.14 (d, 2H), 7.92(d, 2H), 7.51 (t, 2H), 7.46 (d. 2H), 7.35 (t, 1H), 7.32 (d, 2H), 7.12(d, 2H), 7.03 (d, 1H), 5.34 (b, 2H); HPLC-MS calculated for C₂₇H₁₈ClN₇O(M + H⁺): 492.1, found: 492.2. 91

HPLC-MS calculated for C₂₇H₁₇ClN₆O (M + H⁺): 477.1, found: 477.2. 92

¹H NMR (CDCl₃) δ (ppm) 8.71 (d, 1H), 8.34 (s, 1H), 8.15 (d, 2H), 8.00(d, 2H), 7.47~7.52 (m, 5H), 7.34 (t, 1H), 7.32 (d, 2H), 7.12 (d, 2H),2.81 (s, 3H); HPLC-MS calculated for C₂₈H₁₉ClN₆O (M + H⁺): 491.1, found:491.1. 93

¹H NMR (CDCl₃) δ (ppm) 8.40 (s, 1H), 8.34 (s, 1H), 8.15 (d, 2H), 8.03(d, 2H), 7.51 (t, 2H), -7.45 (d, 2H), 7.34 (t, 1H), 7.31 (d, 2H), 7.11(d, 2H); HPLC-MS calculated for C₂₅H₁₆ClN₇O (M + H⁺): 466.1, found:466.1. 94

¹H NMR (CDCl₃) δ (ppm) 8.50 (s, 1H), 8.35 (s, 1H), 8.12 (d, 2H), 8.06(d, 2H), 7.48- 7.54 (m, 4H), 7.37 (t, 1H), 7.34 (d, 2H), 7.11 (d, 2H);HPLC-MS calculated for C₂₅H₁₆ClN₆O₂ (M + H⁺): 467.1, found: 467.1. 95

¹H NMR (CDCl₃) δ (ppm) 10.11 (b, 1H), 8.19 (d, 2H), 7.51~7.57 (m, 6H),7.38~7.47 (m, 8H), 7.18 (d, 2H), 6.65 (b, 1H); HPLC-MS calculated forC₃₀H₂₀ClN₅O₂ (M + H⁺): 518.1, found: 518.1. 96

¹H NMR (CDCl₃) δ (ppm) 8.14 (d, 2H), 7.36~7.57 (m, 12H), 7.33 (d, 2H),7.14 (d, 2H), 4.53 (q, 2H), 1.46 (t, 3H); HPLC-MS calculated forC₃₂H₂₃ClN₄O₃ (M + H⁺): 547.2, found: 547.2 105

¹H NMR (CDCl₃) δ (ppm) 8.15 (s, 1H), 7.70 (d, 2H), 7.56 (t, 2H), 7.29(t, 1H), 7.13 (d, 2H), 7.02 (d, 2H), 6.91 (m, 4H), 2.66 (m, 1H), 1.00(d, 6H); HPLC-MS calculated for C₂₆H₂₁ClN₄O (M + H⁺): 441.1, found441.1. 106

HPLC-MS calculated for C₂₅H₁₉ClN₄O₂ (M + H⁺): 443.0, found 443.0. 107

¹H NMR (CDCl₃, 400 MHz) δ 8.68 (d, 1H), 8.56 (dd, 1H), 8.34 (s, 1H),8.12 (d, 2H), 7.57 (dt, 1H), 7.52 (m, 4H), 7.37 (t, 1H), 7.20 (dd, 1H),7.04 (d, 2H); HPLC-MS calculated for C₂₂H₁₄BrN₅O (M + H⁺) 444.0, found444.1. 108

HPLC-MS calculated for C₂₂H₁₄FN₅O (M + H⁺): 384.1, found: 384.1. 109

¹H NMR (CDCl₃) δ (ppm) 8.18 (s, 1H), 7.40 (d, 2H), 7.27~7.35 (m, 2H),7.12 (t, 1H), 7.00 (bd, 2H), 6.91 (t, 1H), 4.92 (m, 1H), 4.13 (dd, 2H),3.58 (td, 2H), 2.42 (qd, 2H), 1.97 (dd, 2H); HPLC-MS calculated forC₂₂H₁₈BrFN₄O₂ (M + H⁺): 469.1, found: 469.1. 110

¹H NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 8.12 (dd, 2H), 7.61 (d, 2H),7.50 (t, 2H), 7.36 (m, 3H), 7.07 (m, 4H); HPLC-MS calculated forC₂₃H₁₄ClIN₄O (M + H⁺) 525.0, found 524.9. 111

¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.16 (dd, 2H), 7.51 (m, 4H),7.46-7.33 (m, 7H), 7.12 (m, 4H); HPLC-MS calculated for C₂₉H₁₈ClFN₄O(M + H⁺) 493.1, found 493.1. 112

HPLC-MS calculated for C₂₉H₁₈ClFN₄O (M + H⁺) 493.1, found 493.1. 113

¹H NMR (CDCl₃) δ (ppm) 8.33 (s, 1H), 8.12 (d, 2H), 7.47 (t, 2H),7.24~7.35 (m, 3H), 7.06 (t, 1H), 6.99 (d, 2H), 6.89 (t, 1H), 6.77 (d,2H) 3.13 (m, 5H), 1.64 (m, 5H); HPLC-MS calculated for C₂₈H₂₄FN₅O (M +H⁺): 466.2, found: 466.2. 114

¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.16 (dd, 2H), 7.67 (m, 4H),7.54-7.44 (m, 6H), 7.36 (m, 3H), 7.14 (d, 2H); HPLC-MS calculated forC₃₀H₁₈ClF₃N₄O (M + H⁺) 543.1, found 543.1. 115

¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 8.17 (dd, 2H), 7.53-7.48 (m,5H), 7.41-7.32 (m, 7H), 7.13 (d, 2H); HPLC- MS calculated forC₂₇H₁₇ClN₄OS (M + H⁺) 481.1, found 481.1. 116

¹H NMR (CDCl₃, 400 MHz) δ 8.30 (s, 1H), 8.15 (dd, 2H), 7.50 (t, 2H),7.34 (m, 3H), 7.28 (d, 2H), 7.11 (d, 2H), 6.73 (d, 2H), 3.52 (t, 4H),3.12 (t, 4H), 2.78 (s, 3H); HPLC-MS calculated for C₂₈H₂₅ClN₆O (M + H⁺)497.2, found 497.1. 117

HPLC-MS calculated for C₂₈H₂₃Cl₃N₄O (M + H⁺): 537.1, found: 537.1. 118

¹H NMR (MeOD) δ (ppm) 8.47 (s, 1H), 8.11 (d, 2H), 7.47 (t, 2H),7.28-7.34 (m, 4H), 7.22 (d, 2H), 7.07-7.13-7.23 (m, 4H), 3.78 (s, 4H);HPLC- MS calculated for C₂₆H₁₉Cl₃N₄O (M + H⁺): 509.1, found: 509.1. 119

HPLC-MS calculated for C₃₁H₂₇Cl₃N₄O₂ (M + H⁺): 593.1, found: 593.1. 120

HPLC-MS calculated for C₃₁H₂₈Cl₃N₅O (M + H⁺): 592.1, found: 592.1. 121

HPLC-MS calculated for C₃₀H₂₅Cl₃N₄O₂ (M + H⁺): 579.1 found: 579.1. 122

¹H NMR (methanol-d₄) δ (ppm) 8.97 (s, 1H), 8.68 (d, 1H), 8.49 (m, 2H),7.83 (m, 3H), 7.67 (d, 2H), 7.57 (m, 4H), 7.51 (m, 1H), 7.36 (m, 4H);HPLC-MS calculated for C₂₈H₁₈ClN₅O (M + H⁺): 476.1, found 476.1. 123

¹H NMR (CD₃OD, 400 MHz) δ 8.28 (s, 1H), 8.16 (dd, 2H), 7.54 (t, 2H),7.39 (m, 3H), 7.25 (m, 4H), 6.77 (d, 2H), 3.22 (t, 4H), 1.63 (m, 6H);HPLC-MS calculated for C₂₈H₂₄ClN₅O (M + H⁺) 482.2, found 482.1. 124

¹H NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 8.12 (dd, 2H), 7.51 (t, 2H),7.42-7.33 (m, 5H), 7.20 (d, 2H), 7.08 (d, 2H); HPLC-MS calculated forC₂₃H₁₄BrClN₄O (M + H⁺) 477.0, found 477.0. 125

¹H NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 8.14 (d, 2H), 7.51 (t, 2H), 7.36(m, 5H), 7.29 (d, 2H), 7.17 (t, 1H), 7.10 (d, 2H), 7.00 (d, 2H), 6.83(d, 2H); HPLC-MS calculated for C₂₉H₁₉ClN₄O₂ (M + H⁺) 491.1, found491.1. 126

¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H), 8.09 (d, 2H), 7.67 (d, 2H), 7.52(t, 2H), 7.36 (m, 3H), 7.27 (d, 2H), 7.13 (m, 3H), 3.53 (t, 4H), 3.16(t, 4H); HPLC-MS calculated for C₂₇H₂₃BrN₆O (M + H⁺) 527.1, found 527.1.127

¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H), 8.09 (d, 2H), 7.67 (d, 2H), 7.52(t, 2H), 7.36 (t, 1H), 7.27 (d, 2H), 7.05 (m, 4H), 3.50 (t, 4H), 3.08(t, 4H); HPLC-MS calculated for C₂₇H₂₂BrFN₆O (M + H⁺) 545.1, found545.0. 128

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.08 (d, 2H), 7.49 (t, 2H), 7.36(t, 1H), 7.22~7.7.32 (m, 4H), 7.08-7.12 (m, 3H); HPLC-MS calculated forC₂₃H₁₃BrClFN₄O (M + H⁺): 495.0, found: 495.0. 129

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.08 (d, 2H), 7.48 (t, 3H),7.26-7.36 (m, 5H), 7.09 (d, 1H), 6.95 (b, 1H); HPLC-MS calculated forC₂₃H₁₃BrCl₂N₄O (M + H⁺): 511.0, found: 511.0. 130

HPLC-MS calculated for C₂₇H₂₁ClFN₅O₂ (M + H⁺): 502.1, found: 502.1. 131

¹H NMR (CDCl₃) δ (ppm) 8.33 (s, 1H), 8.11 (d, 2H), 7.48 (t, 2H), 7.34(t, 1H), 7.26~7.29 (m, 3H), 7.06 (d, 2H), 6.78 (d, 1H), 6.69 (dd, 1H),3.84 (t, 4H), 3.17 (t, 4H); HPLC-MS calculated for C₂₇H₂₁Cl₂N₅O₂ (M +H⁺): 518.1, found: 518.1. 132

¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.12 (d, 2H), 7.52 (t, 2H),7.33~7.50 (m, 8H), 7.29 (d, 2H), 7.12~7.15 (m, 3H); HPLC-MS calculatedfor C₂₉H₁₈ClFN₄O (M + H⁺): 492.1, found: 492.1. 133

HPLC-MS calculated for C₂₉H₁₈Cl₂N₄O (M + H⁺): 509.1, found: 509.1. 134

¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 8.16 (dd, 2H), 7.74 (s, 1H),7.51 (t, 2H), 7.48 (t, 1H), 7.39-7.32 (m, 7H), 7.12 (d, 2H), 6.67 (d,1H); HPLC-MS calculated for C₂₇H₁₇ClN₄O₂ (M + H⁺) 465.1, found 465.0.135

¹H NMR (CDCl₃, 400 MHz) δ 8.86 (d, 1H), 8.65 (dd, 1H), 8.34 (s, 1H),8.15 (dd, 2H), 8.04 (d, 1H), 7.56-7.50 (m, 7H), 7.36 (m, 3H), 7.14 (d,2H); HPLC-MS calculated for C₂₈H₁₈ClN₅O (M + H⁺) 476.1, found 476.1. 136

¹H NMR (CDCl₃, 400 MHz) δ 8.76 (d, 2H), 8.36 (s, 1H), 8.12 (dd, 2H),7.94 (d, 2H), 7.65 (d, 2H), 7.58 (d, 2H), 7.52 (t, 2H), 7.38 (t, 1H),7.35 (d, 2H), 7.14 (d, 2H); HPLC- MS calculated for C₂₈H₁₈ClN₅O (M + H⁺)476.1, found 476.1. 137

¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.15 (dd, 2H), 7.52 (t, 2H),7.39 (m, 3H), 7.34 (d, 2H), 7.16 (d, 2H), 7.12 (d, 2H), 2.38 (s, 3H),2.23 (s, 3H); HPLC-MS calculated for C₂₈H₂₀ClN₅O₂ (M + H⁺) 494.1, found494.1. 138

¹H NMR (CDCl₃, 400 MHz) δ 8.17 (s, 1H), 7.55 (d, 2H), 7.50 (d, 2H), 7.44(t, 2H), 7.37 (m, 3H), 7.31 (d, 2H), 7.10 (d, 2H), 4.97 (m, 1H), 4.15(dd, 2H), 3.61 (td, 2H), 2.45 (ddd, 2H), 1.99 (dd, 2H); HPLC-MScalculated for C₂₈H₂₃ClN₄O₂ (M + H⁺) 483.2, found 483.1. 139

¹H NMR (CDCl₃, 400 MHz) δ 8.30 (s, 1H), 8.15 (d, 2H), 7.61 (d, 2H), 7.57(t, 2H), 7.42 (m, 4H), 7.31 (m, 3H), 7.23 (dd, 1H), 7.04 (td, 1H);HPLC-MS calculated for C₂₆H₁₆ClFN₆O (M + H⁺) 483.1, found 483.1. 140

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.13 (d, 2H), 7.93 (d, 2H), 7.51(t, 2H), 7.40 (d, 2H), 7.36 (t, 1H), 7.31 (d, 2H), 7.08 (d, 2H), 3.91(s, 3H); HPLC-MS calculated for C₂₅H₁₇ClN₄O₃ (M + H⁺): 457.1, found:457.1. 141

HPLC-MS calculated for C₂₁H₁₈BrN₅O₂ (M + H⁺) 452.1, found 452.0. 142

HPLC-MS calculated for C₂₄H₂₅BrN₆O (M + H⁺) 493.1, found 493.1. 143

HPLC-MS calculated for C₂₆H₁₇ClN₆O (M + H⁺) 465.1, found 465.1. 144

HPLC-MS calculated for C₂₉H₂₇ClN₆O (M + H⁺) 511.2, found 511.1. 145

HPLC-MS calculated for C₂₃H₁₃BrClFN₄O (M + H⁺): 495.0, found: 495.0. 146

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.13 (d, 2H), 7.93 (d, 2H), 7.50(t, 2H), 7.40 (d, 2H), 7.36 (t, 1H), 7.31 (d, 2H), 7.08 (d, 2H), 4.37(q, 2H), 1.39 (t, 3H); HPLC-MS calculated for C₂₆H₁₉ClN₄O₃ (M + H⁺):471.1, found: 470.1. 147

HPLC-MS calculated for C₂₉H₁₈ClFN₄O (M + H⁺): 493.1, found: 493.1. 148

HPLC-MS calculated for C₂₇H₂₁ClFN₅O₂ (M + H⁺): 502.1.0, found: 502.1.501.94 149

¹H NMR (CDCl₃) δ (ppm) 8.32 (s, 1H), 8.11 (d, 2H), 7.52 (t, 2H), 7.39(t, 1H), 7.36 (d, 2H), 7.11 (d, 2H), 7.07 (d, 2H), 6.79 (t, 1H), 3.69(d, 2H), 3.53 (d, 2H), 3.33 (t, 2H), 3.05 (t, 2H), 2.89 (s, 3H); HPLC-MScalculated for C₂₈H₂₄ClFN₆O (M + H⁺): 515.2, found: 515.2. 150

¹H NMR (CDCl₃) δ (ppm) 8.31 (s, 1H), 8.11 (d, 2H), 7.52 (t, 2H), 7.39(t, 1H), 7.36 (d, 2H), 7.11 (d, 2H), 7.07 (d, 2H), 6.79 (t, 1H), 3.53-3.62 (m, 5H), 3.36 (t, 2H), 3.08 (t, 2H), 1.40 (d, 6H); HPLC-MScalculated for C₃₀H₂₈ClFN₆O (M + H⁺): 543.2, found: 543.2. 151

¹H NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.17 (dd, 2H), 7.53 (t, 2H),7.39-7.32 (m, 5H), 7.26 (m, 2H), 7.23 (m, 3H), 7.14 (m, 3H), 2.18 (s,3H); HPLC-MS calculated for C₃₀H₂₁ClN₄O (M + H⁺) 489.1, found 489.1. 152

¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 8.17 (dd, 2H), 7.52 (t, 2H),7.48 (d, 2H), 7.41-7.32 (m, 8H), 7.19 (d, 1H), 7.13 (d, 2H), 2.41 (s,3H); HPLC-MS calculated for C₃₀H₂₁ClN₄O (M + H⁺) 489.1, found 489.1. 153

¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 8.17 (dd, 2H), 7.51 (t, 2H),7.47 (d, 2H), 7.45 (d, 2H), 7.39 (d, 2H), 7.35 (m, 3H), 7.24 (d, 2H),7.13 (d, 2H), 2.39 (s, 3H); HPLC-MS calculated for C₃₀H₂₁ClN₄O (M + H⁺)489.1, found 489.1. 154

HPLC-MS calculated for C₂₈H₂₄ClFN₆O (M + H⁺): 515.2, found: 515.2. 155

HPLC-MS calculated for C₃₀H₂₈ClFN₆O (M + H⁺): 543.2, found: 543.2. 156

HPLC-MS calculated for C₂₈H₂₄Cl₂N₆O (M + H⁺): 531.1, found: 531.1. 157

HPLC-MS calculated for C₃₀H₂₈Cl₂N₆O (M + H⁺): 559.2, found: 559.2. 158

HPLC-MS calculated for C₂₄H₁₇ClN₄O₂ (M + H⁺) 429.1, found 429.2. 159

HPLC-MS calculated for C₂₄H₁₇ClN₄O₂ (M + H⁺) 429.1, found 429.2. 160

HPLC-MS calculated for C₂₄H₁₇ClN₄O (M + H⁺) 413.1, found 413.2. 161

HPLC-MS calculated for C₂₄H₁₄ClF₃N₄O (M + H⁺) 467.1, found 467.2. 162

¹H NMR (CDCl₃, 400 MHz) δ 8.17 (s, 1H), 8.08 (dd, 2H), 7.52 (m, 4H),7.36 (t, 1H), 7.30 (d, 2H), 3.30 (t, 4H), 3.06 (t, 4H), 2.76 (s, 3H);HPLC-MS calculated for C₂₂H₂₁ClN₆O₃S (M + H⁺) 485.1, found 485.2. 163

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O (M + H⁺): 481.9, found 481.9 164

¹H NMR (CDCl₃) δ (ppm) 7.72 (s, 1H), 7.28 (m, 6H), 7.19 (m, 3H), 7.08(m, 2H), 6.97 (b, 1H), 5.27 (d, 2H); HPLC-MS calculated for C₂₄H₁₅C₁₃N₄O(M + H⁺): 481.0, found 481.0. 165

HPLC-MS calculated for C₂₃H₁₃BrCl₂N₄O (M + H⁺): 510.9, found 510.9. 166

HPLC-MS calculated for C₂₀H₁₃BrCl₂N₄O (M + H⁺): 474.9, found 474.9. 167

HPLC-MS calculated for C₂₄H₁₂Cl₃N₅O (M + H⁺): 492.1, found 492.1. 168

¹H NMR (CDCl₃) δ (ppm) 8.12 (s, 1H), 7.71 (d, 2H), 7.57 (t, 2H), 7.47(m, 4H), 7.38 (m, 1H), 7.33 (m, 5H), 7.14 (d, 2H); HPLC-MS calculatedfor C₂₇H₁₇ClN₄OS (M + H⁺): 481.0, found 481.0. 169

¹H NMR (CDCl₃) δ (ppm) 7.54 (m, 3H), 7.42 (m, 4H), 7.45 (b, 1H), 7.10(m,4H), 2.56 (s, 3H); HPLC-MS calculated for C₂₄H₁₅BrCl₂N₄O (M + H⁺):524.9, found 524.9. 170

¹H NMR (CDCl₃) δ (ppm) 7.56 (m, 3H), 7.40 (m, 2H), 7.24 (m, 4H), 7.06(m, 3H), 2.85 (q, 2H), 1.32 (t, 3H); HPLC-MS calculated for C₂₅H₁₇C₁₃N₄O(M + H⁺): 495.0, found 495.0. 171

¹H NMR (methanol-d₄) δ (ppm) 8.69 (d, 2H), 8.49 (s, 1H), 8.04 (d, 2H),7.81 (m, 4H), 7.60 (m, 4H), 7.51 (m, 1H), 7.35 (m, 4H); HPLC- MScalculated for C₂₈H₁₈ClN₅O (M + H⁺): 476.2, found 476.2. 172

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.67 (d, 2H), 7.54 (t, 2H), 7.43(m, 3H), 7.29 (t, 2H), 7.07 (m, 3H), 6.88 (t, 1H); HPLC-MS calculatedfor C₂₃H₁₄BrFN₄O (M + H⁺): 461.0, found 461.0. 173

HPLC-MS calculated for C₂₉H₁₉ClN₄O (M + H⁺): 475.1, found 475.1. 174

HPLC-MS calculated for C₂₃H₁₄Cl₂N₄O (M + H⁺): 433.1, found 433.1. 175

¹H NMR (DMSO-d₆) δ (ppm) 8.65 (s, 1H), 7.77 (d, 2H), 7.62 (m, 4H), 7.42(m, 6H); HPLC-MS calculated for C₂₃H₁₃C₁₃N₄O (M + H⁺): 467.0, found467.0. 176

¹H NMR (CDCl₃) δ (ppm) 8.04 (s, 1H), 7.58 (d, 2H), 7.47 (t, 2H), 7.38(m, 3H), 7.22 (d, 1H), 7.15 (b, 1H), 7.07 (m, 2H), 6.91 (b, 1H); HPLC-MScalculated for C₂₃H₁₃BrCl₂N₄O (M + H⁺): 511.0, found 511.0. 177

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.72 (d, 2H), 7.55 (m, 4H), 7.44(m, 5H), 7.34 (m, 5H), 7.15 (d, 2H); HPLC-MS calculated forC₂₃H₁₃BrCl₂N₄O (M + H⁺): 475.1, found 475.1. 178

¹H NMR (CDCl₃) δ (ppm) 8.19 (s, 1H), 7.86 (m, 4H), 7.45 (d, 2H), 7.33(d, 1H), 7.17 (m, 3H), 6.97 (b, 1H); HPLC-MS calculated forC₂₄H₁₂BrCl₂N₅O (M + H⁺): 535.8, found 535.8. 179

¹H NMR (CDCl₃) δ (ppm) 8.13 (s, 1H), 7.66 (m, 3H), 7.50 (m, 3H), 7.42(m, 2H), 7.22 (m, 1H), 7.12 (d, 1H), 6.88 (dd, 1H); HPLC-MS calculatedfor C₂₄H₁₄BrF₃N₄O (M + H⁺): 511.0, found 511.0. 180

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.70 (d, 2H), 7.55 (t, 2H), 7.45(m, 3H), 7.08 (m, 6H), 2.24 (s, 3H); HPLC-MS calculated for C₂₄H₁₇BrN₄O(M + H⁺): 457.0, found 457.0. 181

¹H NMR (CDCl₃) δ (ppm) 8.09 (s, 1H), 7.65 (d, 2H), 7.46 (m, 6H), 7.16(m, 1H), 7.02 (m, 4H), 2.26 (s, 3H); HPLC-MS calculated for C₂₄H₁₇BrN₄O(M + H⁺): 457.0, found 457.0. 182

¹H NMR (CDCl₃) δ (ppm) 8.09 (s, 1H), 7.69 (d, 2H), 7.55 (t, 2H), 7.46(m, 3H), 7.22 (m, 2H), 2.05 (d, 2H), 6.72 (d, 2H), 3.76 (s, 3H); HPLC-MScalculated for C₂₄H₁₇BrN₄O₂ (M + H⁺): 473.1, found 473.1. 183

¹H NMR (CDCl₃) δ (ppm) 8.13 (s, 1H), 7.66 (d, 2H), 7.55 (t, 2H), 7.46(m, 3H), 7.06 (m, 5H); HPLC-MS calculated for C₂₃H₁₃BrF₂N₄O (M + H⁺):479.0, found 479.0. 184

¹H NMR (CDCl₃) δ (ppm) 8.13 (s, 1H), 7.68 (d, 2H), 7.56 (t, 2H), 7.47(m, 3H), 7.15 (dd, 1H), 7.01 (m, 3H), 6.82 (t, 1H), 2.16 (s, 3H);HPLC-MS calculated for C₂₄H₁₆BrFN₄O (M + H⁺): 475.0, found 475.0. 185

HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O₃ (M + H⁺): 511.9, found 511.9. 186

HPLC-MS calculated for C₂₁H₁₁Cl₃N₄O₂ (M + H⁺): 456.9, found 456.9. 187

HPLC-MS calculated for C₂₄H₁₂F₃Cl₃N₄O (M + H⁺): 534.9, found 534.9. 188

HPLC-MS calculated for C₂₃H₁₁Cl₃F₂N₄O (M + H⁺): 502.9, found 502.9. 189

HPLC-MS calculated for C₂₆H₁₉Cl₃N₄O (M + H⁺): 525.0, found 525.0. 190

HPLC-MS calculated for C₂₄H₁₁Cl₃F₃N₄O2 (M + H⁺): 550.9, found 550.9. 191

HPLC-MS calculated for C₂₅H₁₇Cl₃N₄O (M + H⁺): 494.9, found 494.9. 192

HPLC-MS calculated for C₂₄H₁₁Cl₃F₃N₄O2 (M + H⁺): 550.9, found 550.9. 193

HPLC-MS calculated for C₂₅H₁₇Cl₃N₄O (M + H⁺): 494.9, found 494.9. 194

HPLC-MS calculated for C₂₃H₁₃BrCl₂N₄O (M + H⁺): 510.9, found 510.9. 195

HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O3 (M + H⁺): 511.9, found 511.9. 196

HPLC-MS calculated for C₂₄H₁₂Cl₃N₅O (M + H⁺): 492.0, found 492.0. 197

HPLC-MS calculated for C₂₁H₁₁Cl₃N₄O2 (M + H⁺): 456.9, found 456.9. 198

HPLC-MS calculated for C₂₃H₁₁Cl₃F₃N₄O (M + H⁺): 502.9, found 502.9. 199

HPLC-MS calculated for C₂₅H₁₇Cl₃N₄O₂ (M + H⁺): 511.0, found 511.9. 200

HPLC-MS calculated for C₂₃H₁₄ClFN₄O (M + H⁺): 417.0, found 417.0. 201

HPLC-MS calculated for C₂₄H₄Cl₃FN₄O2 (M + H⁺): 514.9, found 514.9. 202

HPLC-MS calculated for C₂₄H₁₂F₃Cl₃N₄O (M + H⁺): 534.9, found 534.9. 203

¹H NMR (CDCl₃) δ (ppm) 8.21 (s, 1H), 7.71 (d, 2H), 7.57 (t, 2H), 7.48(m, 3H), 7.22 (m, 4H), 7.05 (d, 2H), 1.25 (s, 9H); HPLC-MS calculatedfor C₂₇H₂₃BrN₄O (M + H⁺): 499.0, found 499.0. 204

¹H NMR (CDCl₃) δ (ppm) 8.12 (s, 1H), 7.68 (d, 2H), 7.57 (m, 3H), 7.48(m, 3H), 7.17 (m, 1H), 7.05 (m, 3H), 6.99 (m, 1H); HPLC-MS calculatedfor C₂₃H₁₄BrFN₄O (M + H⁺): 461.0, found 461.0. 205

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.68 (d, 2H), 7.56 (m, 4H), 7.48(t, 1H), 7.33 (d, 2H), 7.10 (d, 2H), 7.01 (d, 2H); HPLC-MS calculatedfor C₂₃H₁₄ClIN₄O (M + H⁺): 525.1, found 525.1. 206

¹H NMR (CDCl₃) δ (ppm) 8.15 (s, 1H), 7.70 (d, 2H), 7.57 (t, 2H), 7.48(t, 1H), 7.38 (m, 6H), 7.14 (d, 2H), 7.04 (m, 2H), 6.80 (m, 1H); HPLC-MScalculated for C₂₉H₁₇ClF₂N₄O (M + H⁺): 511.0, found 511.0. 207

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.72 (d, 2H), 7.57 (t, 2H), 7.48(t, 1H), 7.43 (m, 2H), 7.35 (m, 6H), 7.20 (m, 1H), 7.14 (m, 3H); HPLC-MScalculated for C₂₉H₁₈ClFN₄O (M + H⁺): 493.0, found 493.0. 208

¹H NMR (CDCl₃) δ (ppm) 8.14 (s, 1H), 7.72 (d, 2H), 7.57 (t, 2H), 7.45(m, 3H), 7.35 (m, 6H), 7.22 (m, 1H), 7.15 (d, 2H), 7.05 (m, 1H); HPLC-MScalculated for C₂₉H₁₈ClFN₄O (M + H⁺): 493.0, found 493.0. 209

¹H NMR (CDCl₃) δ (ppm) 8.14 (s, 1H), 7.72 (d, 2H), 7.57 (t, 2H), 7.48(m, 3H), 7.40 (m, 2H), 7.34 (m, 4H), 7.13 (m, 4H); HPLC-MS calculatedfor C₂₉H₁₈ClFN₄O (M + H⁺): 493.0, found 493.0. 210

HPLC-MS calculated for C₂₂H₁₂Cl₃N₄O (M + H⁺): 467.9, found 467.9. 211

HPLC-MS calculated for C₂₂H₁₂Cl₃N₄O (M + H⁺): 467.9, found 467.9. 212

HPLC-MS calculated for C₂₂H₁₂Cl₃N₄O (M + H⁺): 467.9, found 467.9. 213

HPLC-MS calculated for C₂₃H₁₂Cl₃FN₄O (M + H⁺): 484.9, found 484.9. 214

HPLC-MS calculated for C₂₃H₁₂Cl₃FN₄O (M + H⁺): 484.9, found 484.9. 215

HPLC-MS calculated for C₃₀H₂₂Cl₃N₅O₃ (M + H⁺): 605.9, found 605.9. 216

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺): 497.1, found 497.1. 217

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺): 497.1, found 497.1. 218

HPLC-MS calculated for C₂₃H₁₁Cl₃F₃N₄O (M + H⁺): 502.9, found 502.9. 219

HPLC-MS calculated for C₂₃H₁₁Cl₃F₃N₄O (M + H⁺): 502.9, found 502.9. 220

HPLC-MS calculated for C₂₄H₁₄Cl₄N₄O (M + H⁺): 514.9, found 514.9. 221

HPLC-MS calculated for C₂₄H₁₄Cl₄N₄O (M + H⁺): 514.9, found 514.9. 222

HPLC-MS calculated for C₂₃H₁₁Cl₅N₄O (M + H⁺): 534.9, found 534.9. 223

HPLC-MS calculated for C₂₃H₁₁Cl₅N₄O (M + H⁺): 534.9, found 534.9. 224

HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O₃ (M + H⁺): 511.9, found 511.9. 225

HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O₃ (M + H⁺): 511.9, found 511.9. 226

HPLC-MS calculated for C₂₆H₁₇Cl₃N₄O₃ (M + H⁺): 539.0, found 539.0. 227

HPLC-MS calculated for C₂₆H₁₇Cl₃N₄O₃ (M + H⁺): 539.0, found 539.0. 228

HPLC-MS calculated for C₂₇H₁₈Cl₃N₅O₂ (M + H⁺): 550.0, found 550.0. 229

HPLC-MS calculated for C₂₇H₁₈Cl₃N₅O₂ (M + H⁺): 550.0, found 550.0. 230

HPLC-MS calculated for C₂₄H₁₄Cl₃FN₅O (M + H⁺): 498.9, found 498.9. 231

HPLC-MS calculated for C₂₄H₁₄Cl₃FN₅O (M + H⁺): 498.9, found 498.9. 232

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺): 497.0, found 497.0. 233

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺): 497.0, found 497.0. 234

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₃S (M + H⁺): 544.9, found 544.9. 235

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₃S (M + H⁺): 544.9, found 544.9. 236

HPLC-MS calculated for C₂₅H₁₈Cl₃N₄O (M + H⁺): 510.0, found 510.0. 237

HPLC-MS calculated for C₂₅H₁₈Cl₃N₄O (M + H⁺): 510.0, found 510.0. 238

HPLC-MS calculated for C₂₃H₁₂Cl₄N₄O (M + H⁺): 500.9, found 500.9. 239

HPLC-MS calculated for C₂₅H₁₇Cl₃N₄O (M + H⁺): 495.0, found 495.0. 240

HPLC-MS calculated for C₂₅H₁₇Cl₃N₄O (M + H⁺): 495.0, found 495.0. 241

HPLC-MS calculated for C₂₆H₁₇Cl₃N₄O₃ (M + H⁺): 539.0, found 539.0. 242

HPLC-MS calculated for C₂₆H₁₇Cl₃N₄O₃ (M + H⁺): 539.0, found 539.0. 243

HPLC-MS calculated for C₂₄H₁₆Cl₃N₅O (M + H⁺): 496.0, found 496.0. 244

HPLC-MS calculated for C₂₄H₁₅C_(l3)N₄O (M + H⁺): 480.9, found 480.9. 245

HPLC-MS calculated for C₂₄H₁₃BrF₄N₄O (M + H⁺): 529.0, found 529.0. 246

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.70 (d, 2H), 7.55 (t, 2H), 7.45(m, 3H), 7.18 (d, 2H), 7.04 (d, 4H), 2.58 (q, 2H), 1.17 (t, 3H); HPLC-MScalculated for C₂₅H₁₉BrN₄O (M + H⁺): 471.0, found 471.0. 247

¹H NMR (CDCl₃) δ (ppm) 7.54 (m, 3H), 7.40 (m, 4H), 7.23 (d, 1H), 7.18(b, 1H), 7.09 (m, 2H), 6.93 (b, 1H), 2.81 (m, 2H), 1.34 (t, 3H); HPLC-MScalculated for C₂₅H₁₉BrN₄O (M + H⁺): 539.0, found 539.0. 248

¹H NMR (CDCl₃) δ (ppm) 8.14 (s, 1H), 7.70 (d, 2H), 7.56 (t, 2H), 7.46(m, 3H), 7.17 (d, 2H), 7.02 (m, 4H), 2.52 (t, 2H), 1.57 (q, 2H), 0.88(t, 3H); HPLC-MS calculated for C₂₅H₁₉BrN₄O (M + H⁺): 485.1, found485.1. 249

¹H NMR (CDCl₃) δ (ppm) 8.15 (s, 1H), 7.63 (m, 3H), 7.45 (d, 2H), 7.32(m, 2H), 7.19 (m, 3H), 6.98 (b, 1H); HPLC-MS calculated forC₂₄H₁₂BrCl₂F₃N₄O₂ (M + H⁺): 595.0, found 595.0. 250

¹H NMR (CDCl₃) δ (ppm) 8.02 (s, 1H), 7.44 (d, 2H), 7.31 (m, 1H), 7.23(m, 1H), 7.10 (d, 2H), 7.01 (m, 5H), 3.82 (s. 3H), 2.36 (s, 3H), 2.27(s, 3H); HPLC-MS calculated for C₂₆H₂₁BrN₄O₂ (M + H⁺): 501.1, found501.1. 251

¹H NMR (CDCl₃) δ (ppm) 8.22 (s, 1H), 8.11 (s, 1H), 7.97 (d, 1H), 7.76(m, 1H), 7.71 (t, 1H), 7.47 (d, 2H), 7.15 (d, 2H), 7.05 (t, 4H), 2.31(s, 3H); HPLC-MS calculated for C₂₅H₁₆BrN₅O (M + H⁺): 482.0, found482.0. 252

HPLC-MS calculated for C₂₄H₁₂BrClN₅O (M + H⁺): 501.0, found 501.0. 253

¹H NMR (CDCl₃) δ (ppm) 7.55 (m, 3H), 7.41 (m, 4H), 7.07 (d, 2H), 7.00(d, 2H), 6.95 (d, 2H), 2.81 (q, 2H), 2.48 (t, 2H), 1.53 (m, 2H), 1.31(t, 3H), 0.85 (t, 3H); HPLC-MS calculated for C₂₈H₂₅BrN₄O (M + H⁺):513.1, found 513.1. 254

¹H NMR (CDCl₃) δ (ppm) 7.58 (m, 3H), 7.48 (m, 4H), 7.08 (d, 2H), 7.01(d, 2H), 6.97 (d, 2H), 2.81 (q, 2H), 2.54 (q, 2H), 1.30 (t, 3H), 1.14(t, 3H); HPLC-MS calculated for C₂₇H₂₃BrN₄O (M + H⁺): 499.1, found499.1. 255

¹H NMR (CDCl₃) δ (ppm) 7.58 (m, 3H), 7.43 (m, 6H), 7.31 (d, 2H), 7.02(d, 2H), 2.84 (q, 2H), 1.32 (t, 3H); HPLC-MS calculated forC₂₆H₁₈BrF₃N₄O (M + H⁺): 539.1, found 539.1. 256

¹H NMR (CDCl₃) δ (ppm) 8.14 (s, 1H), 7.44 (d, 2H), 7.27 (m, 4H), 7.10(m, 2H), 6.98 (d, 2H), 3.82 (s. 3H), 2.34 (s, 3H); HPLC-MS calculatedfor C₂₅H₁₇BrCl₂N₄O₂ (M + H⁺): 555.0, found 555.0. 257

¹H NMR (CDCl₃) δ (ppm) 7.55 (m, 3H), 7.42 (m, 4H), 7.06 (d, 2H), 7.01(d, 2H), 6.95 (d, 2H), 2.79 (q, 2H), 2.25 (s, 3H), 1.32 (t, 3H); HPLC-MScalculated for C₂₆H₂₁BrN₄O (M + H⁺): 485.1, found 485.1. 258

¹H NMR (CDCl₃) δ (ppm) 8.17 (s, 1H), 7.67 (d, 2H), 7.55 (t, 2H), 7.46(t, 1H), 7.28 (m, 2H), 7.13 (m, 3H), 6.87 (d, 1H), 6.68 (d, 1H), 2.29(s, 3H); HPLC-MS calculated for C₂₄H₁₆ClFN₄O (M + H⁺): 431.1, found431.1. 259

¹H NMR (CDCl₃) δ (ppm) 8.29 (s, 1H), 7.65 (d, 2H), 7.57 (t, 2H), 7.50(d, 1H), 7.46 (t, 1H), 7.39 (d, 1H), 7.30 (d, 2H), 7.19 (d, 1H), 7.12(d, 2H); HPLC-MS calculated for C₂₄H₁₃ClF₄N₄O (M + H⁺): 485.1, found485.1. 260

¹H NMR (CDCl₃) δ (ppm) 8.16 (s, 1H), 7.66 (d, 2H), 7.53 (t, 2H), 7.45(t, 1H), 7.24 (m, 2H), 7.06 (b, 2H), 6.89 (d, 2H), 6.82 (d, 1H), 2.24(s, 3H), 2.23 (s, 3H); HPLC-MS calculated for C₂₅H₁₉ClN₄O (M + H⁺):427.1, found 427.1. 262

¹H NMR (CDCl₃) δ (ppm) 8.01 (s, 1H), 7.46 (d, 2H), 7.37 (t, 2H), 7.29(t, 1H), 7.11 (d, 2H), 7.03 (d, 1H), 6.91 (m, 3H), 6.74 (dd, 1H);HPLC-MS calculated for C₂₃H₁₃Cl₂FN₄O (M + H⁺): 451.1, found 451.1. 262

¹H NMR (CDCl₃) δ (ppm) 8.17 (s, 1H), 7.68 (d, 2H), 7.57 (t, 2H), 7.49(m, 3H), 7.41 (d, 2H), 7.33 (d, 2H), 7.11 (d, 2H); HPLC-MS calculatedfor C₂₄H₁₄ClF₃N₄O (M + H⁺): 467.1, found 467.1. 263

¹H NMR (CDCl₃) δ (ppm) 8.20 (s, 1H), 7.70 (d, 2H), 7.56 (t, 2H), 7.48(t, 1H), 7.32 (d, 2H), 7.16 (d, 2H), 7.10 (d, 2H), 7.02 (d, 2H), 2.29(s, 3H); HPLC-MS calculated for C₂₄H₁₇ClN₄O (M + H⁺): 413.1, found413.1. 264

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.70 (d, 2H), 7.56 (t, 2H), 7.45(t, 1H), 7.28 (d, 2H), 7.17 (d, 2H), 7.09 (d, 2H), 7.01 (d, 2H), 2.51(t, 2H), 1.56 (q, 2H), 0.87 (t, 3H); HPLC-MS calculated for C₂₆H₂₁ClN₄O(M + H⁺): 441.1, found 441.1. 265

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.70 (d, 2H), 7.56 (t, 2H), 7.46(t, 1H), 7.30 (d, 2H), 7.18 (d, 2H), 7.10 (d, 2H), 7.04 (d, 2H), 2.58(q, 2H), 1.17 (t, 3H); HPLC-MS calculated for C₂₅H₁₉ClN₄O (M + H⁺):427.1, found 427.1. 266

HPLC-MS calculated for C₂₅H₁₇ClN₄O₃ (M + H⁺): 456.9., found 456.9. 267

¹H NMR (CDCl₃) δ (ppm) 7.58 (m, 3H), 7.48 (m, 2H), 7.41 (m, 6H), 7.32(m, 3H), 7.27 (d, 2H), 7.12 (d, 2H), 2.87 (q, 2H), 1.32 (t, 3H); HPLC-MScalculated for C₃₁H₂₃ClN₄O (M + H⁺): 503.2, found 503.2. 268

¹H NMR (CDCl₃) δ (ppm) 8.08 (s, 1H), 7.71 (d, 2H), 7.56 (t, 2H), 7.46(t, 1H), 7.28 (d, 2H), 7.15 (d, 2H), 7.08 (d, 2H), 6.97 (d, 2H), 2.39(d, 2H), 1.78 (m, 1H), 0.82 (d, 6H); HPLC-MS calculated for C₂₇H₂₃ClN₄O(M + H⁺): 455.2, found 455.2. 269

¹H NMR (methanol-d₄) δ (ppm) 8.69 (m, 1H), 8.50 (s, 1H), 8.29 (m, 1H),8.10 (d, 1H), 7.82 (m, 4H), 7.72 (m, 1H), 7.59 (m, 4H), 7.51 (m, 1H),7.35 (m, 4H); HPLC- MS calculated for C₂₈H₁₈ClN₅O (M + H⁺): 476.1, found476.1. 270

¹H NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 8.07 (d, 1H), 7.87 (d, 1H), 7.79(t, 1H), 7.61 (t, 1H), 7.33-7.27 (m, 4H), 7.22 (d, 2H), 6.97 (d, 1H).HPLC-MS calculated for C₂₃H₁₂Cl₃N₅O₃ (M + H⁺) 512.0, found 512.0. 271

¹H NMR (DMSO, 400 MHz) δ 8.78 (s, 1H), 8.15 (d, 2H), 7.97-7.95 (m, 2H),7.90 (m, 3H), 7.84 (dd, 1H), 7.78 (m, 1H), 7.30 (d, 2H), 6.00 (s, 2H).HPLC-MS calculated for C₂₃H₁₄Cl₃N₅O (M + H⁺) 482.0, found 482.0. 272

HPLC-MS calculated for C₂₃H₁₃Cl₂N₅O₃ (M + H⁺) 478.0, found 478.0. ¹H NMR(CDCl₃, 400 MHz) δ 8.53 (d, 2H), 8.39 (m, 3H), 7.37 (d, 2H), 7.30 (m,4H), 7.08 (d, 2H). HPLC-MS calculated for C₂₃H₁₃Cl₂N₅O₃ (M + H⁺) 478.0,found 478.0. 273

HPLC-MS calculated for C₂₃H₁₃Cl₂N₅O₃ (M + H⁺) 478.0, found 478.0. ¹H NMR(CDCl₃, 400 MHz) δ 8.38 (s, 1H), 8.09 (d, 1H), 7.87 (d, 1H), 7.79 (t,1H), 7.62 (t, 1H), 7.35 (d, 2H), 7.20 (m, 4H), 7.08 (d, 2H). HPLC-MScalculated for C₂₃H₁₃Cl₂N₅O₃ (M + H⁺) 478.0, found 478.0. 274

HPLC-MS calculated for C₂₃H₁₅Cl₂N₅O (M + H⁺) 448.1, found 448.1. 275

HPLC-MS calculated for C₂₃H₁₂Cl₃FN₄O (M + H⁺) 485.0, found 485.0. 276

HPLC-MS calculated for C₂₈H₂₃Cl₃N₆O (M + H⁺) 565.1, found 565.1. 277

HPLC-MS calculated for C₂₄H₁₅BrCl₂N₄OS (M + H⁺) 557.0, found 557.0. 278

¹HNMR (CDCl₃, 400 MHz) δ 8.05 (d, 2H), 7.59-7.40 (m, 5H), 7.35 (m, 1H),7.21 (dd, 2H), 7.16 (d, 1H), 6.98 (m, 1H), 3.54 (s, 3H). HPLC-MScalculated for C₂₄H₁₅BrCl₂N₄O₃S (M + H⁺) 591.0, found 591.0. 279

HPLC-MS calculated for C₂₄H₁₃Cl₃N₄O₃ (M + H⁺) 511.0, found 511.0. 280

¹H NMR (dioxane, 400 MHz) δ 8.33 (s, 1H), 8.00 (d, 2H), 7.45 (s, 1H),7.39 (d, 2H), 7.16 (d, 1H), 7.29-7.19 (m, 5H), 7.03 (m, 1H), 4.53 (d,2H), 3.71 (t, 1H). HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺) 497.0,found 497.0. 281

¹H NMR (CDCl₃, 400 MHz) δ 8.36 (s, 1H), 8.28 (d, 2H), 7.57 (d, 2H),7.36-7.29 (m, 3H), 7.23-7.16 (m, 2H), 7.03 (m, 1H), 3.97 (m, 3H), 3.48(m, 2H), 2.83 (m, 6H). HPLC- MS calculated for C₂₉H₂₃Cl₃N₆O₂ (M + H⁺)593.1, found 593.1. 282

HPLC-MS calculated for C₂₈H₂₀Cl₃N₅O₃ (M + H⁺) 580.1, found 580.1. 283

HPLC-MS calculated for C₂₉H₂₂Cl₃N₅O₂ (M + H⁺) 578.1, found 578.1. 284

¹H NMR (CDCl₃, 400 MHz) δ 8.34 (s, 1H), 8.06 (d, 2H), 7.44 (m, 2H),7.34-7.28 (m, 3H), 7.18 (m, 2H), 7.03 (m, 1H), 5.31 (s, 2H), 3.66 (m,2H), 2.89 (m, 6H), 2.71 (s, 3H). HPLC-MS calculated for C₂₉H₂₅Cl₃N₆O(M + H⁺) 579.1, found 579.1. 285

HPLC-MS calculated for C₂₄H₁₅C₁₃N₄OS (M + H⁺) 513.0, found 513.0. 286

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₃S (M + H⁺) 545.0, found 545.0. 287

¹H NMR (CDCl₃, 400 MHz) δ 7.54 (m, 4H), 7.47 (m, 1H), 7.42 (d, 2H), 7.30(d, 4H), 7.08 (d, 2H), 3.17 (q, 2H), 2.90 (s, 3H), 1.03 (t, 3H). HPLC-MScalculated for C₂₇H₂₁ClF₃N₅O (M + H⁺) 524.1, found 524.1. 288

HPLC-MS calculated for C₂₆H₁₉ClF₃N₅O (M + H⁺) 510.1, found 510.1. 289

¹H NMR (CDCl₃, 400 MHz) δ 7.64 (m, 5H), 7.52 (d, 2H), 7.38 (m, 4H), 7.12(d, 2H). HPLC-MS calculated for C₂₅H₁₃ClF₃N₅O (M + H⁺) 492.1, found492.1. 290

HPLC-MS calculated for C₂₃H₁₂BrCl₃N₄O (M + H⁺) 545.0, found 545.0. 291

HPLC-MS calculated for C₂₆H₂₀Cl₃N₅O (M + H⁺) 524.1, found 524.1. 292

HPLC-MS calculated for C₂₇H₂₀Cl₃N₅O₂ (M + H⁺) 552.1, found 552.1. 293

HPLC-MS calculated for C₂₈H₂₃Cl₃N₆O (M + H⁺) 565.1, found 565.1. 294

HPLC-MS calculated for C₂₇H₂₂Cl₃N₅O₂ (M + H⁺) 554.1, found 554.1. 295

HPLC-MS calculated for C₂₄H₁₇Cl₃N₆O (M + H ⁺) 511.1, found 511.1. 296

HPLC-MS calculated for C₂₆H₂₀Cl₃N₅O₂ (M + H⁺) 540.1, found 540.1. 297

HPLC-MS calculated for C₂₄H₁₅Cl₃N₄O₂ (M + H⁺) 497.0, found 497.0. 298

HPLC-MS calculated for C₂₃H₁₃Br₂ClN₄O (M + H⁺) 557.0, found 557.0. 299

HPLC-MS calculated for C₂₆H₂₂ClN₇O (M + H⁺) 484.2, found 484.2. 300

HPLC-MS calculated for C₂₆H₂₂ClN₇O (M + H⁺) 484.2, found 484.2. 301

HPLC-MS calculated for C₂₉H₁₉ClN₄O (M + H⁺) 475.1, found 475.2. 302

¹H NMR (CDCl₃, 400 MHz) δ 8.42 (d, 2H), 7.48 (t, 2H), 7.39 (t, 1H), 7.32(d, 2H), 7.26 (d, 2H), 7.11 (m, 4H), 2.86 (m, 1H), 1.22 (s, 3H), 1.20(s, 3H); HPLC-MS calculated for C₂₆H₂₁ClN₄O (M + H⁺) 441.1, found 441.2.307

¹H NMR (CDCl₃, 400 MHz) δ 7.65 (d, 2H), 7.54 (t, 2H), 7.47 (t, 1H), 7.27(d, 2H), 7.16 (d, 2H), 7.09 (d, 2H), 7.02 (d, 2H), 4.19 (s, 3H), 2.80(m, 1H), 1.16 (s, 3H), 1.14 (s, 3H); HPLC-MS calculated for C₂₇H₂₃ClN₄O(M + H⁺) 455.2, found 455.2. 308

¹H NMR (CDCl₃, 400 MHz) δ 8.37 (d, 2H), 7.46 (t, 2H), 7.35 (t, 1H), 7.32(d, 2H), 7.25 (d, 2H), 7.10 (m, 4H), 4.37 (s, 3H), 2.86 (m, 1H), 1.21(s, 3H), 1.19 (s, 3H); HPLC-MS calculated for C₂₇H₂₃ClN₄O (M + H⁺)455.2, found 455.2. 309

HPLC-MS calculated for C₃₂H₃₁ClN₄O₃ (M + H⁺) 555.2, found 555.2. 310

¹H NMR (CD₃OD, 400 MHz) δ 8.37 (d, 2H), 7.45 (t, 2H), 7.36 (t, 1H), 7.30(d, 2H), 7.24 (d, 2H), 7.09 (m, 4H), 5.35 (s, 2H), 2.85 (m, 1H), 1.48(s, 9H), 1.21 (s, 3H), 1.19 (s, 3H); HPLC-MS calculated for C₃₂H₃₁ClN₄O₃(M + H⁺) 555.2, found 555.2. 312

¹H NMR (CDCl₃, 400 MHz) δ 8.38 (d, 2H), 7.49 (t, 2H), 7.40 (m, 3H), 7.35(d, 2H), 7.21 (d, 2H), 7.11 (d, 2H); HPLC-MS calculated forC₂₃H₁₄BrClN₄O (M + H⁺) 477.0, found 477.0. 313

¹H NMR (CDCl₃, 400 MHz) δ 8.44 (d, 2H), 7.50-7.42 (m, 5H), 7.38 (d, 2H),7.24 (d, 2H), 7.14 (d, 2H), 3.77 (s, 3H); HPLC-MS calculated forC₂₄H₁₆BrClN₄O₃S (M + H⁺) 555.0, found 555.0. 315

¹H NMR (CDCl₃, 400 MHz) δ 8.37 (s, 1H), 8.09 (d, 2H), 7.61 (d, 2H), 7.53(t, 2H), 7.46 (d, 1H), 7.41 (t, 1H), 7.38 (d, 2H), 7.31 (d, 2H), 7.15(m, 3H), 2.64 (s, 3H); HPLC-MS calculated for C₂₇H₁₉ClN₆O (M + H⁺)479.1, found 479.1. 316

¹H NMR (CDCl₃, 400 MHz) δ 8.94 (s, 1H), 8.35 (s, 1H), 8.10 (d, 2H), 7.54(m, 4H), 7.37 (m, 5H), 7.12 (m, 3H), 2.47 (s, 3H); HPLC-MS calculatedfor C₂₇H₁₉ClN₆O (M + H⁺) 479.1, found 479.1. 317

¹H NMR (CDCl₃, 400 MHz) δ 8.39 (dd, 2H), 7.57-7.50 (m, 7H), 7.46-7.38(m, 5H), 7.34 (d, 2H), 7.15 (d, 2H); HPLC- MS calculated forC₂₉H₁₈ClN₃O₂ (M + H⁺) 476.1, found 476.1. 319

¹H NMR (CDCl₃, 400 MHz) δ 8.84 (d, 1H), 8.21 (dd, 2H), 8.00 (t, 1H),7.92 (d, 2H), 7.82 (d, 1H), 7.56 (m, 4H), 7.49 (t, 1H), 7.44 (t, 1H),7.34 (d, 2H), 7.16 (d, 2H), 2.56 (s, 3H); HPLC-MS calculated forC₃₁H₂₀ClN₇O₂ (M + H⁺) 558.1, found 558.1. 321

¹H NMR (CDCl₃, 400 MHz) δ 8.76 (s, 1H), 8.36 (s, 1H), 8.10 (dd, 2H),7.59 (d, 2H), 7.53 (m, 3H), 7.43 (m, 3H), 7.37 (d, 2H), 7.13 (d, 2H),4.06 (s, 2H); HPLC-MS calculated for C₂₈H₁₈ClN₇O (M + H⁺) 504.1, found504.1. 322

¹H NMR (CDCl₃, 400 MHz) δ 8.40 (d, 1H), 8.34 (s, 1H), 8.16 (dd, 2H),7.77 (d, 2H), 7.52 (t, 2H), 7.48-7.30 (m, 8H), 7.14 (d, 2H); HPLC-MScalculated for C₂₈H₁₈ClN₅O₂ (M + H⁺) 492.1, found 492.1. 323

¹H NMR (CDCl₃, 400 MHz) δ 8.37 (s, 1H), 8.10 (d, 2H), 7.58 (d, 2H), 7.53(t, 2H), 7.38 (m, 4H), 7.29 (d, 2H), 7.12 (m, 3H), 2.95 (q, 2H), 1.31(t, 3H); HPLC-MS calculated for C₂₈H₂₁ClN₆O (M + H⁺) 493.2, found 493.2.324

¹H NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.11 (d, 2H), 7.52 (m, 4H), 7.38(m, 3H), 7.21 (d, 2H), 7.12 (d, 2H), 6.76 (s, 1H), 2.48 (s, 3H), 2.34(s, 3H); HPLC-MS calculated for C₂₈H₂₁ClN₆O (M + H⁺) 493.2, found 493.2.325

¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H), 8.08 (d, 2H), 7.52 (m, 4H), 7.35(m, 3H), 7.04 (m, 4H), 3.49 (t, 4H), 3.07 (t, 4H); HPLC-MS calculatedfor C₂₇H₂₂ClFN₆O (M + H⁺) 501.2, found 501.2. 326

¹H NMR (CDCl₃, 400 MHz) δ 8.34 (d, 2H), 7.46 (t, 2H), 7.37 (m, 5H), 7.21(d, 2H), 7.10 (d, 2H), 4.37 (s, 3H); HPLC-MS calculated forC₂₄H₁₆BrClN₄O (M + H⁺) 491.0, found 491.0. 328

¹H NMR (CDCl₃, 400 MHz) δ 8.92 (d, 1H), 8.36 (d, 2H), 8.08 (t, 1H), 7.84(m, 3H), 7.55 (m, 3H), 7.47 (t, 2H), 7.37 (t, 1H), 7.34 (d, 2H), 7.15(d, 2H), 4.39 (s, 3H); HPLC-MS calculated for C₂₉H₂₀ClN₅O (M + H⁺)490.1, found 490.1. 329

¹H NMR (CDCl₃, 400 MHz) δ 8.66 (d, 1H), 7.83 (d, 2H), 7.73 (t, 1H), 7.67(m, 3H), 7.55 (t, 2H), 7.48 (t, 1H), 7.38 (d, 2H), 7.28 (d, 2H), 7.23(dd, 1H), 7.14 (d, 2H), 4.21 (s, 3H); HPLC-MS calculated for C₂₉H₂₀ClN₅O(M + H⁺) 490.1, found 490.1. 331

HPLC-MS calculated for C₂₈H₁₈ClN₅O₂ (M + H⁺) 492.1, found 492.1. 333

¹H NMR (CDCl₃, 400 MHz) δ 8.72 (d, 2H), 8.10 (d, 2H), 7.60-7.49 (m, 8H),7.45 (t, 1H), 7.37 (d, 2H), 7.17 (d, 2H), 3.55 (s. 3H); HPLC-MScalculated for C₂₉H₂₀ClN₅O₃S (M + H⁺) 554.1, found 554.1. 335

¹H NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.19 (d, 1H), 8.13(d, 2H), 7.52 (t, 2H), 7.45 (d, 2H), 7.37 (t, 1H), 7.34 (d, 2H), 7.22(d, 2H), 7.18 (d, 1H), 7.12 (d, 2H), 2.21 (s, 3H); HPLC-MS calculatedfor C₂₉H₂₀ClN₅O₂ (M + H⁺) 506.1, found 506.1. 336

¹H NMR (CDCl₃, 400 MHz) δ 8.54 (d, 2H), 8.09 (d, 2H), 7.68 (d, 2H), 7.53(m, 6H), 7.45 (t, 1H), 7.37 (d, 2H), 7.16 (d, 2H), 3.55 (s, 3H); HPLC-MScalculated for C₂₉H₂₀ClN₅O₄S (M + H⁺) 570.1, found 570.1. 339

¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 8.16 (d, 2H), 7.87 (d, 2H), 7.52(m, 3H), 7.42 (d, 2H), 7.36 (t, 1H), 7.32 (d, 2H), 7.12 (d, 2H), 7.07(d, 1H), 6.51 (d, 1H); HPLC-MS calculated for C₂₈H₁₉ClN₆O (M + H⁺)491.1, found 491.1. 340

HPLC-MS calculated C₂₄H₁₄BrClN₄O₃ (M + 1⁺): 520.0, found: 520.0. 341

¹H NMR (CDCl₃) δ (ppm) 8.10 (d, 2H), 7.50 (t, 2H), 7.41 (m, 3H), 7.34(d, 2H), 7.20 (d, 2H), 7.09 (d, 2H), 4.52 (q, 2H), 1.45 (t, 3H). HPLC-MScalculated C₂₆H₁₈BrClN₄O₃ (M + 1⁺): 549.0, found: 549.0. 342

¹H NMR (CDCl₃) δ (ppm) 9.95 (b, 1H), 8.16 (d, 2H), 7.51 (t, 2H), 7.41(m, 5H), 7.22 (d, 2H), 7.13 (d, 2H), 3.05 (d, 3H). HPLC-MS calculatedC₂₅H₁₇BrClN₅O₂ (M + 1⁺): 534.0, found: 534.0. 343

HPLC-MS calculated C₂₆H₁₉BrClN₅O₂ (M + 1⁺): 548.0, found: 548.0. 344

HPLC-MS calculated C₂₈H₂₁BrClN₅O₃ (M + 1⁺): 590.1, found: 590.1. 345

HPLC-MS calculated C₂₉H₂₄BrClN₆O₂ (M + 1⁺): 603.1, found: 603.1. 346

HPLC-MS calculated C₂₉H₂₃BrClN₅O₂ (M + 1⁺): 588.1, found: 588.1. 347

¹H NMR (CDCl₃) δ (ppm) 8.10 (d, 2H), 7.51 (t, 2H), 7.41 (m, 3H), 7.33(d, 2H), 7.19 (d, 2H), 7.09 (d, 2H), 5.38 (m, 1H), 1.44 (d, 6H). HPLC-MScalculated C₂₇H₂₀BrClN₄O₃ (M + 1⁺): 563.0, found: 563.1. 348

¹H NMR (CDCl₃) δ (ppm) 8.12 (d, 2H), 7.50 (t, 2H), 7.41 (m, 3H), 7.33(d, 2H), 7.19 (d, 2H), 7.09 (d, 2H), 1.67 (s, 9H). HPLC-MS calculatedC₂₈H₂₂BrClN₄O₃ (M + 1⁺): 577.1, found: 577.1. 349

HPLC-MS calculated C₂₇H₂₂ClN₅O₂ (M + 1⁺): 484.2, found: 484.2. 350

¹H NMR (CDCl₃) δ (ppm) 8.13 (d, 2H), 7.51 (t, 2H), 7.39 (t, 1H), 7.30(d, 2H), 7.24 (d, 2H), 7.10 (d, 2H), 4.52 (q, 2H), 2.85 (m, 1H), 1.45(t, 3H), 1.19 (d, 6H). HPLC-MS calculated C₂₉H₂₅ClN₄O₃ (M + 1⁺): 513.2,found: 513.2. 351

¹H NMR (CDCl₃) δ (ppm) 8.21 (d, 2H), 7.54 (t, 2H), 7.42 (t, 1H), 7.32(d, 2H), 7.29 (d, 2H), 7.12 (m, 4H), 2.87 (m, 1H), 2.55 (s, 3H). 1.20(d, 6H). HPLC-MS calculated C₂₉H₂₃ClN₆O₂ (M + 1⁺): 523.2, found: 523.352

¹H NMR (CDCl₃) δ (ppm) 8.68 (d, 1H), 8.15 (d, 2H), 8.01 (d, 2H), 7.63(d, 1H), 7.49 (m, 4H), 7.32 (m, 3H), 7.11 (d, 2H), 2.73 (s, 3H). HPLC-MScalculated C₂₈H₁₈Cl₂N₆OS (M + 1⁺): 557.1, found: 557.1. 353

¹H NMR (CDCl₃) δ (ppm) 8.23 (d, 1H), 8.12 (d, 2H), 8.01 (d, 2H), 7.52(m, 4H), 7.33 (m, 3H), 7.23 (d, 1H), 7.11 (d, 2H), 2.73 (s, 3H). HPLC-MScalculated C₂₈H₂₀ClN₇OS (M + 1⁺): 538.1, found: 538.1. 354

HPLC-MS calculated C₂₈H₂₄ClN₅O₂ (M + 1⁺): 498.2, found: 498.2. 355

¹H NMR (CDCl₃) δ (ppm) 8.13 (d, 2H), 7.54 (t, 2H). 7.44 (t, 1H), 7.33(d, 2H), 7.25 (d, 2H), 7.10 (m, 4H), 2.87 (m, 1H). 1.20(d, 6H). HPLC-MScalculated C₂₇H₂₀ClN₅O (M + 1⁺): 466.1, found: 466.1. 356

¹H NMR (CDCl₃) δ (ppm) 8.69 (d, 1H), 8.09 (d, 2H), 8.03 (d, 2H), 7.64(d, 1H), 7.54 (t, 3H), 7.50 (d, 2H), 7.44 (t, 1H), 7.34 (d, 2H), 7.15(d, 1H), 3.53 (s, 3H). HPLC-MS calculated C₂₈H₁₈Cl₂N₆O₃S (M + 1⁺):589.1, found: 589.1. 357

¹H NMR (CDCl₃) δ (ppm) 8.36 (d, 1H), 8.11 (d, 2H), 7.94 (d, 2H), 7.54(t, 2H), 7.45 (m, 3H), 7.34 (d, 2H), 7.15 (d, 2H), 7.03(d, 1H), 5.34 (b,2H), 3.55 (s, 3H). HPLC-MS calculated C₂₈H₂₀ClN₇O₃S (M + 1⁺): 570.1,found: 570.1. 358

HPLC-MS calculated C₂₆H₁₆BrClN₆O₂ (M + 1⁺): 559.0, found: 559.0. 359

¹H NMR (CDCl₃) δ (ppm) 9.77 (b, 1H), 8.25 (d, 1H), 8.15 (d, 2H), 8.03(d, 2H), 7.54 (m, 5H), 7.42 (d, 1H), 7.39 (d, 2H), 7.19 (d, 1H), 7.16(d, 2H), 6.80 (b, 2H), 5.91 (b, 1H). HPLC-MS calculated C₂₈H₁₉ClN₈O₂(M + 1⁺): 535.1, found: 535.1. 360

HPLC-MS calculated C₂₉H₂₅ClN₄O₂ (M + 1⁺): 497.2, found: 497.2. 361

HPLC-MS calculated C₂₉H₂₇ClN₄O₂ (M + 1⁺): 499.2, found: 499.2. 362

¹H NMR (CDCl₃) δ (ppm) 8.33 (s, 1H), 8.17 (d, 2H), 7.70 (d, 2H), 7.51(t, 2H), 7.38 (m, 4H), 7.11 (d, 2H), 6.54 (d, 1H), 3.97 (s, 3H). HPLC-MScalculated C₂₇H₁₉ClN₆O (M + 1⁺): 479.1, found: 479.1. 363

¹H NMR (CDCl₃) δ (ppm) 9.19 (b, 1H), 8.34 (s, 1H), 8.15 (d, 2H), 8.02(d, 2H), 7.84 (d, 1H), 7.51 (m, 5H), 7.33 (m, 3H), 7.15 (d, 2H). HPLC-MScalculated C₂₇H₁₇ClN₆O (M + 1⁺): 477.1, found: 477.1. 364

¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.14 (d, 2H), 7.52 (t, 3H), 7.43(d, 2H), 7.34 (m, 5H), 7.13 (d, 2H), 6.33 (d, 1H), 3.87 (s, 3H). HPLC-MScalculated C₂₇H₁₉ClN₆O (M + 1⁺): 479.1, found: 479.1. 365

¹H NMR (CDCl₃) δ (ppm) 8.81 (d, 2H), 8.34 (t, 3H), 8.17 (d, 2H), 7.49(m, 4H), 7.86 (d, 2H), 7.52 (t, 2H), 7.36 (t, 1H), 7.31 (d, 2H), 7.24(t, 1H), 7.13 (d, 2H). HPLC-MS calculated C₂₇H₁₇ClN₆O (M + 1⁺): 477.1,found: 477.1. 366

¹H NMR (CDCl₃) δ (ppm) 8.34 (s, 1H), 8.32 (b, 1H), 8.15 (d, 2H), 7.99(b, 1H), 7.86 (d, 2H), 7.52 (t, 2H), 7.46 (d, 2H), 7.37 (t, 1H), 7.31(d, 2H), 7.12 (d, 2H). HPLC-MS calculated C₂₇H₁₈ClN₇O (M + 1⁺): 492.1,found: 492.1. 367

¹H NMR (CDCl₃) δ (ppm) 8.84 (d, 1H), 8.68 (d, 1H), 8.36 (s, 1H), 8.14(d, 2H), 7.94 (d, 2H), 7.53 (m, 4H), 7.37 (t, 1H), 7.33 (d, 2H), 7.13(d, 2H). HPLC-MS calculated C₂₈H₁₆ClN₇O (M + 1⁺): 502.1, found: 502.1.368

¹H NMR (CDCl₃) δ (ppm) 8.35 (m, 2H), 8.16 (d, 2H), 7.49 (m, 6H), 7.35(m, 3H), 7.14 (d, 2H), 2.58 (s, 3H), 2.52 (s, 3H). HPLC-MS calculatedC₂₉H₂₁ClN₆O (M + 1⁺): 505.2, found: 505.2. 369

¹H NMR (CDCl₃) δ (ppm) 8.70 (s, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.14(d, 2H), 7.51 (t, 2H), 7.35 (m, 7H), 7.12 (d, 2H). HPLC-MS calculatedC₂₆H₁₆ClN₅O₂ (M + 1⁺): 466.1, found: 466.1. 370

¹H NMR (CDCl₃) δ (ppm) 8.35 (s, 1H), 8.12 (d, 2H), 7.65 (d, 2H), 7.55(m, 5H), 7.39 (t, 1H), 7.33 (d, 2H), 7.16 (s, 1H), 7.07 (d, 2H). HPLC-MScalculated C₂₇H₁₉ClN₆O (M + 1⁺): 479.1, found: 479.1. 371

¹H NMR (CDCl₃) δ (ppm) 9.02 (d, 1H), 8.67 (t, 1H), 8.55 (d, 1H), 8.35(s, 1H), 8.15 (d, 2H), 7.95 (d, 2H), 7.51 (m, 4H), 7.37 (t, 1H), 7.33(d, 2H), 7.14 (d, 2H). HPLC-MS calculated C₂₇H₁₇ClN₆O (M + 1⁺): 477.1,found: 477.1. 372

HPLC-MS calculated C₂₇H₂₄N₄O (M + 1⁺): 421.2, found: 421.2. 373

HPLC-MS calculated C₂₇H₂₁F₃N₄O (M + 1⁺): 475.2, found: 475.2. 374

HPLC-MS calculated C₂₇H₂₃ClN₄O (M + 1⁺): 455.2, found: 455.2. 375

HPLC-MS calculated C₂₆H₂₀F₂N₄O (M + 1⁺): 443.2, found: 443.2. 376

HPLC-MS calculated C₂₆H₂₀C_(l2)N₄O (M + 1⁺): 475.1, found: 475.1. 377

¹H NMR (CDCl₃) δ (ppm) 8.15 (d, 2H), 7.59 (t, 2H), 7.49 (t, 1H), 7.43(d, 2H), 7.37 (d, 2H), 7.21 (d, 2H), 7.10 (d, 2H), 2.87 (m, 1H). HPLC-MScalculated C₂₂H₁₃BrClN₅O (M + 1⁺): 478.0, found: 478.0. 378

HPLC-MS calculated C₂₆H₂₁FN₄O (M + 1⁺): 425.2, found: 425.2. 379

HPLC-MS calculated C₂₆H₂₁ClN₄O (M + 1⁺): 441.1, found: 441.2. 380

HPLC-MS calculated C₂₆H₂₁BrN₄O (M + 1⁺): 485.1, found: 485.1. 381

¹H NMR (CDCl₃) δ (ppm) 8.19 (d, 2H), 7.58 (t, 2H). 7.48 (t, 1H), 7.34(d, 2H), 7.25 (d, 2H), 7.11 (m, 4H), 2.87 (m, 1H). 1.20 (d, 6H). HPLC-MScalculated C₂₅H₂₀ClN₅O (M + 1⁺): 442.1, found: 442.1. 382

HPLC-MS calculated for C₃₀H₁₉ClN₄O₃ (M + H⁺): 519.1, found 519.1. 383

¹H NMR (CDCl₃) δ (ppm) 8.67 (s, 1H), 8.29 (t, 1H), 8.15 (br s, 1H), 8.02(d, 1H), 7.98 (d, 1H), 7.71 (t, 1H), 7.64 (d, 2H), 7.58 (d, 3H), 7.46(br s, 2H), 7.44 (m, 6H), 7.37 (m, 1H); HPLC-MS calculated forC₃₀H₂₀ClN₅O₂ (M + H⁺): 518.1, found 518.1. 384

¹H NMR (CDCl₃) δ (ppm) 7.64-7.54 (m, 3H), 7.51-7.45 (m, 4H), 7.44-7.38(m, 4H), 7.37-7.30 (m, 4H), 7.28 (s, 1H), 7.13 (d, 2H), 5.92 (br s, 1H),4.48 (s, 2H), 2.99 (s, 3H); HPLC-MS calculated for C₃₁H₂₄ClN₅O₃S (M +H⁺): 582.1, found 582.1. 385

HPLC-MS calculated for C₃₂H₂₃ClN₄O₃ (M + H⁺): 547.1, found 547.1. 386

1H NMR (CDCl₃) δ (ppm) 7.65-7.53 (m, 5H), 7.49 (d, 2H), 7.41-7.39 (m,4H), 7.37- 7.31 (m, 3H), 7.29-7.24 (m, 2H, partially obscured by CHCl₃),7.16 (d, 2H), 4.43 (br s, 2H), 3.35 (br s, 3H); HPLC- MS calculated forC₃₁H₂₃ClN₄O₃S (M + H⁺): 567.1, found 567.1. 387

HPLC-MS calculated for C₃₀H₂₀BrClN₄O (M + H⁺): 567.1, found 567.1. 388

HPLC-MS calculated for C₃₃H₂₄ClN₅O₂ (M + H⁺): 568.1, found 568.1. 389

HPLC-MS calculated for C₃₅H₂₃ClN₆O₂ (M + H⁺): 595.1, found 595.1. 390

¹H NMR (CDCl₃) δ (ppm) 8.26 (s, 1H), 8.22 (s, 1H), 7.87 (d, 1H), 7.63(t, 1H), 7.52 (d, 2H), 7.48-7.40 (m, 4H), 7.39-7.30 (m, 5H), 7.14 (d,2H), 6.11 (d, 1H), 3.98 (m, 1H), 2.03 (d, 2H), 1.74 (d, 2H), 1.64 (d,1H), 1.42 (m, 2H), 1.23 (m, 3H). HPLC-MS calculated for C₃₆H₃₀ClN₅O₂(M + H⁺): 600.1, found 600.1. 391

¹H NMR (CDCl₃) δ (ppm) 9.94 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.29(s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.72 (t, 1H), 7.49 (d, 2H), 7.45(d, 2H), 7.39 (t, 2H), 7.35-7.29 (m, 5H), 7.25 (br s, 1H), 7.14 (d, 2H);HPLC-MS calculated for C₃₀H₂₀ClN₅O₂ (M + H⁺): 585.1, found 585.1. 392

HPLC-MS calculated for C₃₄H₂₉ClN₆O₂ (M + H⁺): 589.1, found 589.1. 393

HPLC-MS calculated for C₃₄H₂₉ClN₆O₂ (M + H⁺): 577.1, found 577.1. 394

¹H NMR (CDCl₃) δ (ppm) 8.08 (s, 1H), 7.69 (d, 2H), 7.55 (t, 2H), 7.46(m, 3H), 7.21 (m, 2H), 7.05 (d, 2H), 6.71 (d, 2H), 3.76 (s, 3H); HPLC-MScalculated for C₂₄H₁₇BrN₄O₂ (M + H⁺): 472.1, found 472.1. 395

HPLC-MS: calculated for C₂₅H₁₉ClN₄O₂ (M + 1⁺): 443.1, found 443.1 396

HPLC-MS: calculated for C₂₄H₁₅ClN₄O₃ (M + 1⁺): 443.1, found 443.1. 397

HPLC-MS calculated for C₂₃H₁₄BrClN₄O (M + H⁺): 477.0, found0477.0. 398

HPLC-MS calculated for C₂₈H₁₈ClN₅O (M + H⁺): 465.1, found 465.1. 399

¹H NMR (CDCl₃) δ (ppm) 9.02 (s, 1H), 8.24 (s, 1H), 7.68 (d, 2H), 7.57(m, 6H), 7.42 (m, 3H), 7.36 (d, 2H), 7.15 (d, 2H); HPLC-MS calculatedfor C₂₈H₁₈ClN₅O (M + H⁺): 465.1, found 465.1. 400

¹H NMR (CDCl₃) δ (ppm) 8.17 (s, 1H), 7.72 (d, 2H), 7.58 (t, 2H), 7.48(t, 1H), 7.30 (m, 7H), 7.11 (d, 2H); HPLC- MS calculated for C₂₃H₁₅ClN₄O(M + H⁺): 399.1, found 399.1. 401

HPLC-MS calculated for C₂₅H₁₅ClN₆O₂ (M + H⁺): 467.1, found 467.1. 402

HPLC-MS calculated for C₂₄H₁₇ClN₄O₂ (M + H⁺): 429.1, found 429.1. 403

HPLC-MS calculated for C₂₈H₂₂ClN₅O₂ (M + H⁺): 496.1, found 496.1. 404

HPLC-MS calculated for C₂₇H₂₀ClN₅O₂ (M + H⁺): 482.1, found 482.1. 405

HPLC-MS calculated for C₂₅H₁₆ClN₇O₁ (M + H⁺): 466.1, found 466.1. 406

HPLC-MS calculated for C₂₆H₁₈ClN₇O (M + H⁺): 480.1, found 480.1. 407

HPLC-MS calculated for C₂₆H₁₈ClN₇O (M + H⁺): 480.1, found 480.1. 408

HPLC-MS calculated for C₂₃H₁₅ClN₄O₂ (M + H⁺): 415.1, found 415.1. 409

¹H NMR (CDCl₃) δ (ppm) 8.11 (s, 1H), 7.61 (d, 2H), 7.49 (t, 2H), 7.40(t, 1H), 7.19 (m, 6H), 7.02 (d, 2H), 4.42 (s, 2H); HPLC-MS calculatedfor C₂₄H₁₆Cl₂N₄O (M + H⁺): 447.1, found 447.1. 410

HPLC-MS calculated for C₂₉H₂₆ClN₅O (M + H⁺): 496.2, found 496.2. 411

HPLC-MS calculated for C₂₈H₂₄ClN₅O₂ (M + H⁺): 498.2, found 498.2. 412

HPLC-MS calculated for C₂₈H₂₆ClN₅O (M + H⁺): 484.2, found 484.2. 413

HPLC-MS calculated for C₂₈H₂₆ClN₅O (M + H⁺): 484.2, found 484.2. 414

HPLC-MS calculated for C₂₈H₂₄ClN₅O (M + H⁺): 482.2, found 482.2. 415

HPLC-MS calculated for C₂₇H₂₃ClN₄O₂ (M + H⁺): 471.2, found 471.2. 416

¹H NMR (CDCl₃) δ (ppm) 8.10 (s, 1H), 7.71 (m, 3H), 7.56 (m, 3H), 7.46(t, 2H), 7.30 (m, 2H), 7.11 (m, 3H), 6.62 (m, 1H), 5.74 (d, 1H), 5.30(d, 1H); HPLC-MS calculated for C₂₅H₁₇ClN₄O (M + H⁺): 425.1, found425.1. 417

¹H NMR (CDCl₃) δ (ppm) 8.12 (s, 1H), 7.69 (t, 2H), 7.55 (t, 2H), 7.47(t, 1H), 7.32 (m, 3H), 7.13 (m, 4H), 6.89 (d, 1H), 2.85 (m, 1H), 0.92(d, 2H), 0.66 (d, 2H); HPLC-MS calculated for C₂₆H₁₉ClN₄O (M + H⁺):439.1, found 439.1. 418

HPLC-MS calculated for C₂₇H₂₃ClN₄O₂ (M + H⁺): 471.1, found 471.1. 419

¹H NMR (CDCl₃) δ (ppm) 7.55 (m, 3H), 7.41 (m, 4H), 7.31 (m, 4H), 7.08(m, 2H), 2.79 (q, 2H), 1.33 (t, 3H); HPLC-MS calculated forC₂₆H₁₈ClF₃N₄O (M + H⁺): 494.1, found 494.1. 420

HPLC-MS: calculated for C₂₇H₁₆Cl₂N₆O (M + 1⁺): 511.1, found 511.1. 421

¹H NMR (CDCl₃) δ (ppm) 7.57 (m, 3H), 7.49 (m, 2H), 7.41 (m, 6H), 7.30(m, 4H), 7.28 (m, 1H), 7.13 (d, 2H), 2.55 (s, 3H); HPLC-MS calculatedfor C₃₀H₂₁ClN₄O (M + H⁺): 489.1, found 489.1. 422

HPLC-MS calculated for C₂₅H₁₆BrF₃N₄O (M + H⁺): 525.1, found 525.1. 423

¹H NMR (CDCl₃) δ (ppm) 8.19 (s, 1H), 7.70 (m, 2H), 7.57 (t, 2H), 7.46(t, 1H), 7.30 (d, 2H), 7.18 (d, 2H), 7.09 (d, 2H), 7.04 (d, 2H), 2.43(m, 1H), 1.78 (m, 5H), 1.32 (m, 5H); HPLC-MS calculated for C₂₉H₂₅ClN₄O(M + H⁺): 481.2, found 481.2. 424

HPLC-MS: calculated for C₂₆H₁₆ClN₅O (M + 1⁺): 466.1, found 466.1. 425

HPLC-MS calculated for C₂₄H₁₇ClN₄O (M + H⁺): 413.1, found 413.1. 426

HPLC-MS calculated for C₂₄H₁₇ClN₄O₂ (M + H⁺): 428.1, found 428.1. 427

¹H NMR (CDCl₃) δ (ppm) 8.14 (s, 1H), 7.55 (m, 2H), 7.49 (m, 3H), 7.31(d, 2H), 7.17 (m, 4H), 7.02 (d, 2H), 2.86 (m, 1H), 1.19 (d, 6H); HPLC-MScalculated for C₂₆H₂₁ClN₄O (M + H⁺): 441.1, found 441.1. 428

HPLC-MS: calculated for C₂₄H₁₆Br₂N₄O (M + 1⁺): 535.0, found 535.0. 429

HPLC-MS: calculated for C₂₅H₁₉BrN₄O₂ (M + 1⁺): 487.1, found 487.1. 430

HPLC-MS: calculated for C₂₅H₁₆BrN₅O (M + 1⁺): 482.1, found 482.1. 431

HPLC-MS: calculated for C₂₄H₁₇ClN₄O₃S (M + 1⁺): 477.1, found 477.1. 432

¹H NMR (CDCl₃) δ (ppm) 8.17 (s, 1H), 7.48 (m, 7H), 7.30 (d, 2H), 7.22(d, 2H), 7.01 (d, 2H); HPLC-MS calculated for C₂₃H₁₄BrClN₄O (M + H⁺):477.0, found 477.0. 433

HPLC-MS: calculated for C₃₀H₂₁ClN₄O (M + 1⁺): 489.1, found 489.1. 434

HPLC-MS calculated for C₃₀H₁₈ClN₅O (M + H⁺): 500.1, found 500.1. 435

HPLC-MS calculated for C₃₀H₁₈ClN₅O (M + H⁺): 500.1, found 500.1. 436

HPLC-MS calculated for C₃₀H₁₈ClF₃N₄O₂ (M + H⁺): 559.1, found 559.1. 437

¹H NMR (CDCl₃) δ (ppm) 8.07 (s, 1H), 7.58 (d, 2H), 7.52 (d, 2H), 7.44(m, 4H), 7.35 (m, 7H), 7.15 (d, 2H), 2.43 (s, 3H); HPLC-MS calculatedfor C₃₀H₂₁ClN₄O (M + H⁺): 489.1, found 489.1. 438

¹H NMR (CDCl₃) δ (ppm) 8.00 (s, 1H), 7.51 (d, 2H), 7.41 (m, 4H), 7.31(m, 6H), 7.25 (m, 2H), 7.14 (d, 2H), 6.99 (m, 1H), 3.83 (s, 3H), 2.37(s, 3H); HPLC-MS calculated for C₃₁H₂₃ClN₄O₂ (M + H⁺): 519.2, found519.2. 439

¹H NMR (CDCl₃) δ (ppm) 8.00 (s, 1H), 7.63 (d, 2H), 7.47 (t, 2H), 7.39(m, 1H), 7.24 (m, 3H), 7.07 (m, 3H), 6.81 (d, 2H), 1.72 (m, 1H), 0.90(m, 2H), 0.57 (m, 2H); HPLC-MS calculated for C₂₆H₁₉ClN₄O (M + H⁺):439.1, found 439.1. 440

HPLC-MS: calculated for C₃₀H₂₁ClN₄O (M + 1⁺): 489.1, found 489.1. 441

¹H NMR (CDCl₃) δ (ppm) 8.17 (s, 1H), 7.56 (d, 2H), 7.43 (m, 7H), 7.36(d, 2H), 7.18 (m, 4H), 7.11 (t, 2H); HPLC-MS calculated for C₂₉H₁₈ClFN₄O(M + H⁺): 493.1, found 493.1. 442

HPLC-MS calculated for C₂₉H₁₈ClFN₄O (M + H⁺): 493.1, found 493.1. 443

HPLC-MS calculated for C₂₈H₁₈ClN₅O₂ (M + H⁺): 492.1, found 492.1. 444

HPLC-MS calculated for C₂₉H₁₈ClFN₄O (M + H⁺): 493.1, found 493.1. 445

¹H NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.56 (m, 3H), 7.47 (d, 2H), 7.40(d, 2H), 7.26 (d, 2H), 7.03 (d, 2H), 2.81 (q, 2H), 1.32 (t, 3H); HPLC-MScalculated for C₂₆H₁₈BrCl₃N₄O (M + H⁺): 587.0, found 587.0. 446

¹H NMR (CDCl₃) δ (ppm) 7.84 (d, 2H), 7.58 (m, 3H), 7.42 (m, 4H), 7.25(d, 2H), 7.00 (d, 2H), 3.88 (s, 3H), 2.87 (q, 2H), 1.30 (t, 3H); HPLC-MScalculated for C₂₇H₂₁BrN₄O₃ (M + H⁺): 529.1, found 529.1. 447

¹H NMR (CDCl₃) δ (ppm) 8.19 (s, 1H), 7.95 (m, 2H), 7.72 (d, 2H), 7.61(apparent t, 2H), 7.52 (apparent t, 1H), 7.42 (d, 2H), 7.35 (m, 4H),7.17 (d, 2H), 6.95 (d, 1H); HPLC-MS calculated for C₂₈H₁₉ClN₆O (M + H⁺):491.1, found 491.1. 448

¹H NMR (CDCl₃) δ (ppm) 8.21 (s, 1H), 8.01 (dd, 1H), 7.81 (d, 1H), 7.58(apparent t, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 7.33 (m, 3H), 7.14 (d,2H), 6.98 (d, 1H); HPLC-MS calculated for C₂₈H₁₈ClN₅O₂ (M + H⁺): 492.1,found 492.1.

CB1 Biological Assays

Homogenized membranes are prepared from CHO cell clones stablyexpressing a human cannabinoid receptor 1 (CB1) or human cannabinoidreceptor 2 (CB2). Cells are grown and scrapped from 15 cm tissue cultureplates, and then subsequently centrifuged down. Cells are washed oncewith cold PBS, and resuspended in ≦20 ml of Buffer A (20 mM HEPES, pH7.4, 10 mM EDTA, EDTA-free complete protease inhibitor cocktail [1tablet/25 ml]). The cell suspension is homogenized on ice, using aPolytron homogenizer at 25000 rpm at three intervals of 15 seconds each.The homogenate is first centrifuged at 2000 rpm on a tabletop low speedcentrifuge for 10 minutes. The supernatant, after passing through a cellstrainer, is then centrifuged at 50,000×g for 25 minutes at 4° C. Thepellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4,0.1 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/10ml]). Protein concentration of the prep is determined using the BCAProtein Assay kit using BSA as standard. The membranes are aliquoted andkept frozen at −80° C.

[³H]-CP55940 Ligand Binding Assay:

Solutions of test compounds ranging from 100 μM to 0.01 nM are preparedin DMSO. The desired amount of membrane prep is diluted with ice-coldassay buffer (50 mM Tris-HCl, 2.5 mM EDTA, 5 mM MgCl₂, 0.05% BSA, pH7.4) and vortexed well. 2 μl or less of compound is distributed intoeach well of a round-bottom 96-well polystyrene assay plate, followed byaddition of 100 μl of diluted membranes (3-10 μg/well) and the mixtureis kept on ice until the addition of hot CP55940 (final concentration of0.5 nM). [³H]-CP55940 is diluted 1:6300 (v/v) with cold assay buffer and100 μl is added into each well. The reaction is carried out at roomtemperature for 120 minutes before the membranes are harvested onto aPerkinElmer Unifilter GF/B-96 filter plate using a Packard FiltermateHarvester. After nine washes with wash buffer (50 mM Tris-HCl, 2.5 mMEDTA, 5 mM MgCl₂, 0.05% BSA, pH 7.), the filter is dried in a 37° C.oven for 30 minutes. MicroScint-20 is added and the plate sealed forscintillation counting on TopCount. EC₅₀ values are obtained by fittingthe data with the sigmoidal dose response curve-fitting tool of GraphPadPrism. Eight or twelve different concentrations are used to generate aconcentration response curve (using three data points perconcentration).

GTPγS Binding Assay:

Solutions of test compounds ranging from 100 μM to 0.01 nM are preparedin DMSO. The desired amount of membrane prep is diluted with ice-coldassay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 0.1% Fattyacid-free BSA, 5 μM GDP) and vortexed well. 2 μl or less of compound isdistributed into each well of a round-bottom 96-well polystyrene assayplate, followed by addition of 100 μl of diluted membranes (3-10μg/well) and the mixture is kept on ice until the addition of hot GTPγS.[³⁵S]-GTPγS (Perkin Elmer NEG030H; 1 μCi/μl 1250 Ci/mmol) is diluted1:1000 (v/v) with cold assay buffer and 100 μl is added into each well.The reaction is carried out at room temperature for 90 minutes beforethe membranes are harvested onto PerkinElmer Unifilter GF/B-96 filterplate using a Packard Filtermate Harvester. After several washes withwash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂), and a rinsewith 95% ethanol, the filter is dried in a 37° C. oven for 30 minutes.MicroScint-20 is added and the plate sealed for scintillation countingon TopCount. EC₅₀ values are obtained by fitting the GTP [γ-³⁵S] bindingdata with the sigmoidal dose response curve-fitting tool of GraphPadPrism. Six or twelve different concentrations are used to generate aconcentration response curve (using three data points perconcentration).

For each assay, a Cheng-Prusoff correction (Cheng and Prusoff, 1973,Biochem. Pharmacol., 22: 3099-3103) is used to convert the EC₅₀ toinhibition constant K_(i). Thus,

$K_{i} = \frac{{EC}_{50}}{1 + {\lbrack L\rbrack/K_{d}}}$

where [L] is the concentration of the radio-ligand used in the assay,and K_(d) is the equilibrium binding dissociation constant for theradio-ligand.

Food Intake and Body Weight Gain

To evaluate the efficacy of compounds of the invention on inhibition offood intake and body weight gain, genetically obese (Lep^(ob)/Lep^(ob))mice and diet-induced obese (DIO) mice are used in acute and sub-chronicmodels, respectively.

Male ob/ob mice (age 7-8 weeks old, Jackson Labs, Bar Harbor, Me.) arehoused in groups of four and fed commercial standard pellet diet (LabDiet 5001, PMI Nutrition International, LLC). Diet-induced obese miceare generated using 6-7 weeks old C57BL6 mice (Jackson Labs, Bar Harbor,Me.) placed on high fat diet (D12331, Research Diets) for 12-17 weeks.All mice are maintained on a 12-hour light/dark cycle (lights on at06:00) in a humidity- and temperature-controlled environment with freeaccess to food and water.

The week prior to the start of each study, mice are singly housed and ahabituation to treatment is performed to establish baseline foodconsumption and body weight Animals are randomized into treatment groupsbased on their initial body weight and food consumption.

To determine the acute effects of a single administration of a compoundof the invention (test compound) on food consumption, ob/ob mice aretreated with either vehicle, a known antagonist as a positive control,or with test compound(s). Similarly, to determine more chronic effectsof test compound on food consumption and body weight gain, DIO mice aretreated with either vehicle, a known antagonist as a positive control,or with test compound(s) for up to 7-35 days. Test compounds are dosedat ranges between 0.1 up to 100 mg/kg Animals are treated one hour priorto the start of the dark cycle. Food intake and body weight are recordedmanually using an electronic balance prior to treatment, 16 hourspost-treatment, followed by daily measurements for up to 7-35 days afterthe start of study. Compound efficacy is determined by comparing foodintake and body weight data between vehicle treated, standard positivecontrol treated, and test compound treated mice.

Compounds of Formula I, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Compoundof the invention show a K_(i) of between 1×10⁻⁵ and 1×10⁻¹⁰M, preferablyless than 500 nM, more preferably less than 100 nM. Additionally,compounds of the invention show a 10 fold, preferably 20, 50 and 100fold, selectivity for CB1 over CB2. For example,5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(compound 19) shows a K_(i) of 5 nM and >5 μM for CB1 and CB2,respectively. It is understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and scope of the appended claims. All publications,patents, and patent applications cited herein are hereby incorporated byreference for all purposes.

1. A compound selected from Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii,Ij and Ik:

in which: Y is selected from O, NR₇ and S; wherein R₇ is selected fromhydrogen, hydroxy and C₁₋₆ alkyl; R₁ is selected from C₅₋₁₀ heteroaryl,C₃₋₁₂cyclolalkyl, phenyl and benzyl; wherein said heteroaryl,cycloalkyl, phenyl and benzyl of R₁ is optionally substituted with 1 to3 radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ and R₁₀; R₂ is selected fromC₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl and phenoxy; wherein saidheterocycloalkyl, heteroaryl, phenyl or phenoxy of R₂ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈XR₁₀ and—XR₁₀; wherein each X is independently selected from a bond,C₁₋₄alkylene and C₂₋₄alkenylene; R₃ is selected from hydrogen, halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀,—XS(O)₀₋₂R₉, —XC(O)R₁₀, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈; R₄ isselected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈; R₅ is selected fromhydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene; R₆is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈; R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyland C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆ alkyl, nitro, C₁₋₆ alkyl,C₁₋₆ alkoxy, halo-substituted-C₁₋₆ alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆ alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof; with the proviso that compounds of Formula Ia do not includecompounds of Formula II.
 2. The compound of claim 1 in which: R₁ isselected from phenyl and cyclohexyl; wherein said phenyl and cyclohexylare optionally substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —NR₈R₉,—S(O)₂R₈, —C(O)OR₈ and R₁₀; wherein R₈ and R₉ are independently selectedfrom hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; or R₈ and R₉ together with thenitrogen atom to which both are attached form C₃₋₈heterocycloalkyl orC₅₋₁₀heteroaryl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein said phenyl ofR₁ and heteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈and R₉ and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆ alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.
 3. The compound of claim 2 in which: R₂ isselected from piperazinyl, morpholino, benzthiazolyl, pyridinyl,pyrazolyl, phenyl and phenoxy; wherein said piperazinyl, morpholino,benzthiazolyl, pyridinyl, pyrazolyl, phenyl or phenoxy is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, halo-substituted C₁₋₆ alkoxy, —XNR₈R₉, —XOR₈, —XC(O)R₈,—XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈R₁₀ and XR₁₀; whereineach X is independently selected from a bond, C₁₋₄alkylene andC₂₋₄alkenylene; and R₈ and R₉ are independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atomto which both are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl;and R₁₀ is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl,C₃₋₁₂cycloalkyl and phenyl; wherein said heteroaryl or heterocycloalkylof R₁₀ or the combination of R₈ and R₉ and additionally the cycloalkylor phenyl of R₁₀ is optionally substituted with 1 to 3 radicalsindependently selected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈ and —C(O)OR₈; wherein eachR₈ is independently selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl.4. The compound of claim 3 in which: R₄ is selected from C₁₋₆alkyl,phenyl, C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl,C₃₋₈heterocycloalkyl-carbonyl and C₃₋₁₂cycloalkyl; wherein any phenyl,cycloalkyl, heteroaryl or heterocycloalkyl of R₄ can optionally besubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XS(O)₀₋₂R₈, —XNR₈R₉,—XC(O)NR₈R₉, —XC(O)NR₈R₁₀, —XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉, —XOR₈,—XC(O)R₁₀ and —XC(O)OR₈; wherein each X is independently selected from abond, C₁₋₄alkylene and C₂₋₄alkenylene; each R₈ is independently selectedfrom hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and R₁₀ is selected fromC₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl;wherein said heteroaryl or heterocycloalkyl of R₁₀ or the combination ofR₈ and R₉ and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl; and R₅ is selected from ethoxy, chloro,hydroxy, dimethyl-amino, morpholino-ethoxy, methoxy, amino,hydroxy-ethoxy, dimethyl-amino-ethoxy, hydroxy-ethyl-amino,morpholino-propoxy and methyl-piperazinyl-ethoxy.
 5. The compound ofclaim 4 of Formula Ia:

in which: Y is O; and R₃ is selected from hydrogen, cyano, halo,halo-substituted-C₁₋₆alkyl, cyano-C₁₋₆alkyl, C₁₋₆alkyl, —XS(O)₀₋₂R_(9a),—XC(O)NR_(8a)R_(9a), —XC(O)OR_(8a), —XR₁₀ and —XC(O)R₁₀; wherein eachR_(8a) and R_(9a) are independently selected from hydrogen andC₁₋₆alkyl; or R_(8a) and R_(9a) together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R_(8a) and R_(9a) and additionally the cycloalkyl orphenyl of R₁₀ is optionally substituted with 1 to 3 radicalsindependently selected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl,nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, phenyl, —NR_(8a)R_(8a) and —C(O)OR_(8a);wherein each R_(8a) is independently selected from hydrogen andC₁₋₆alkyl.
 6. The compound of claim 5 in which R₁ is selected fromphenyl and cyclohexyl; wherein said phenyl and cyclohexyl is optionallysubstituted with 1 to 2 radicals independently selected from chloro,bromo, fluoro, methyl, cyano, methyl-sulfanyl, t-butyl,methoxy-carbonyl, butoxy, trifluoromethoxy, trifluoromethyl, methoxy,isopropyl, piperidinyl and phenyl optionally substituted with halo. 7.The compound of claim 6 in which R₂ is selected from piperazinyl,morpholino, pyridinyl, pyrazolyl, benzthiazolyl, phenyl and phenoxy;wherein said piperazinyl, morpholino, pyridinyl, pyrazolyl,benzthiazolyl, phenyl or phenoxy is optionally substituted with 1 to 2radicals independently selected from: bromo; chloro; fluoro; iodo;hydroxy; isopropyl; methyl; cyclohexyl; oxazolyl; isoxazolyl optionallysubstituted with 1 to 2 methyl radicals; pyrazolidinyl; methyl-carbonyl;amino-carbonyl; morpholino; thienyl; furanyl; cyclohexyl-aminooptionally substituted with an amino radical; methyl-sulfonyl;trichloromethyl; methoxy-carbonyl; chloro-methyl; butoxy-ethenyl;butoxy-ethyl; trifluoromethyl; trifluoromethoxy; ethoxy-carbonyl;t-butyl; amino-carbonyl; ethyl; propyl; methoxy; methoxy-methyl;carboxy; piperidinyl; piperidinyl-methyl; morpholino-methyl;diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.
 8. The compound of claim 7 in whichR₃ is selected from hydrogen, methyl, methyl-sulfonyl,t-butoxy-carbonyl-methyl, amino-carbonyl-methyl,methyl-[1,2,4]oxadiazolyl, cyano-methyl, carboxy, ethoxy-carbonyl,methyl-amino-carbonyl, dimethyl-amino-carbonyl, benzyl, furanyl,pyridinyl, indolyl, morpholino-carbonyl, piperidinyl-amino-carbonyl,piperidinyl-carbonyl, isopropoxy-carbonyl, amino-carbonyl,methyl-sulfanyl, methyl-amino-carbonyl, cyano, methyl-sulfonyl,methyl-piperazinyl, benzyl and phenyl optionally substituted with 1 to 2radicals independently selected from methyl, methoxy, fluoro, chloro,bromo, iodo, cyano, nitro, hydroxy-methyl, ethoxy-carbonyl,methyl-sulfonyl, dimethyl-amino, methyl-amino,cyclopropyl-aminocarbonyl, isopropoxy, trifluoromethyl andtrifluoromethoxy.
 9. The compound of claim 8 in which R₄ is methyl,hydroxy-ethyl, t-butyl, phenyl, benzyl, cyclohexyl, cyclopropyl,pyridinyl, furanyl, morpholino-carbonyl, tetrahydro-thiopyranyl,tetrahydro-thiopyranyl 1,1-dioxide and quinolinyl; wherein said phenyl,benzyl, cyclohexyl, cyclopropyl, pyridinyl, furanyl,morpholino-carbonyl, tetrahydro-thiopyranyl, tetrahydro-thiopyranyl1,1-dioxide and quinolinyl of R₄ is optionally substituted with 1 to 2radicals independently selected from methyl, cyano, carboxy,aminocarbonyl, methoxy, trifluoromethyl, isopropoxy, methyl-sulfanyl,dimethyl-amino, ethoxy-carbonyl, trifluoromethoxy,cyclopropyl-aminocarbonyl, pyridinyl-aminocarbonyl,cyclohexyl-aminocarbonyl, isoxazolyl-aminocarbonyl,dimethylamino-ethyl-aminocarbonyl, methoxy-ethyl-aminocarbonyl, nitro,amino, fluoro, chloro, bromo, hydroxymethyl,methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.
 10. The compound of claim 4 of Formula Ic:

in which: Y is O; and R₆ is selected from hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, —XNR₈R₉,—XNR₈S(O)₂R₉, —XR₁₀, —XOXNR₈R₉ and —XNR₈NR₈R₉; wherein each X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene;each R₈ is independently selected from hydrogen, C₁₋₆alkyl andC₂₋₆alkenyl; and R₁₀ is selected from C₅₋₁₀heteroaryl,C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyl and phenyl; wherein saidheteroaryl or heterocycloalkyl of R₁₀ or the combination of R₈ and R₉and additionally the cycloalkyl or phenyl of R₁₀ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, phenyl, —NR₈R₈and —C(O)OR₈; wherein each R₈ is independently selected from hydrogen,C₁₋₆alkyl and C₂₋₆alkenyl.
 11. The compound of claim 10 in which R₁ isselected from phenyl and cyclohexyl; wherein said phenyl and cyclohexylis optionally substituted with 1 to 2 radicals independently selectedfrom chloro, bromo, fluoro, methyl, cyano, methyl-sulfanyl, t-butyl,methoxy-carbonyl, butoxy, trifluoromethoxy, trifluoromethyl, methoxy,isopropyl, piperidinyl and phenyl optionally substituted with halo. 12.The compound of claim 11 in which R₂ is selected from piperazinyl,morpholino, pyridinyl, pyrazolyl, benzthiazolyl, phenyl and phenoxy;wherein said piperazinyl, morpholino, pyridinyl, pyrazolyl,benzthiazolyl, phenyl or phenoxy is optionally substituted with 1 to 2radicals independently selected from: bromo; chloro; fluoro; iodo;hydroxy; isopropyl; methyl; cyclohexyl; oxazolyl; isoxazolyl optionallysubstituted with 1 to 2 methyl radicals; pyrazolidinyl; methyl-carbonyl;amino-carbonyl; morpholino; thienyl; furanyl; cyclohexyl-aminooptionally substituted with an amino radical; methyl-sulfonyl;trichloromethyl; methoxy-carbonyl; chloro-methyl; butoxy-ethenyl;butoxy-ethyl; trifluoromethyl; trifluoromethoxy; ethoxy-carbonyl;t-butyl; amino-carbonyl; ethyl; propyl; methoxy; methoxy-methyl;carboxy; piperidinyl; piperidinyl-methyl; morpholino-methyl;diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.
 13. The compound of claim 12 inwhich R₄ is methyl, hydroxy-ethyl, t-butyl, phenyl, benzyl, cyclohexyl,cyclopropyl, pyridinyl, furanyl, morpholino-carbonyl,tetrahydro-thiopyranyl, tetrahydro-thiopyranyl 1,1-dioxide andquinolinyl; wherein said phenyl, benzyl, cyclohexyl, cyclopropyl,pyridinyl, furanyl, morpholino-carbonyl, tetrahydro-thiopyranyl,tetrahydro-thiopyranyl 1,1-dioxide and quinolinyl of R₄ is optionallysubstituted with 1 to 2 radicals independently selected from methyl,cyano, carboxy, aminocarbonyl, methoxy, trifluoromethyl, isopropoxy,methyl-sulfanyl, dimethyl-amino, ethoxy-carbonyl, trifluoromethoxy,cyclopropyl-aminocarbonyl, pyridinyl-aminocarbonyl,cyclohexyl-aminocarbonyl, isoxazolyl-aminocarbonyl,dimethylamino-ethyl-aminocarbonyl, methoxy-ethyl-aminocarbonyl, nitro,amino, fluoro, chloro, bromo, hydroxymethyl,methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.
 14. The compound of claim 13 in which R₆ isselected from methyl-sulfonyl-aminomethyl, bromomethyl,methyl-sulfonyl-methyl, ethyl(methyl)amino, dimethylamino, methyl,ethyl, cyano, bromo, chloro, fluoro, morpholino, methyl-piperazinyl,dimethyl-amino-ethoxy, methyl-amino-amino and hydroxyethyl(methyl)aminoand methoxy.
 15. The compound of claim 4 selected from Formula Ie, Igand Ih:

in which: Y is O; and R₆ is selected from hydrogen, halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, —XNR₈R₉,—XNR₈S(O)₂R₉, —XR₁₀, —XOXNR₈R₉ and —XNR₈NR₈R₉; wherein each X isindependently selected from a bond and C₁₋₄alkylene; each R₈ and R₉ areindependently selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,phenyl, —NR₈R₈ and —C(O)OR₈; wherein each R₈ is independently selectedfrom hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl.
 16. The compound of claim 15in which R₁ is selected from phenyl and cyclohexyl; wherein said phenyland cyclohexyl is optionally substituted with 1 to 2 radicalsindependently selected from chloro, bromo, fluoro, methyl, cyano,methyl-sulfanyl, t-butyl, methoxy-carbonyl, butoxy, trifluoromethoxy,trifluoromethyl, methoxy, isopropyl, piperidinyl and phenyl optionallysubstituted with halo.
 17. The compound of claim 16 in which R₂ isselected from piperazinyl, morpholino, pyridinyl, pyrazolyl,benzthiazolyl, phenyl and phenoxy; wherein said piperazinyl, morpholino,pyridinyl, pyrazolyl, benzthiazolyl, phenyl or phenoxy is optionallysubstituted with 1 to 2 radicals independently selected from: bromo;chloro; fluoro; iodo; hydroxy; isopropyl; methyl; cyclohexyl; oxazolyl;isoxazolyl optionally substituted with 1 to 2 methyl radicals;pyrazolidinyl; methyl-carbonyl; amino-carbonyl; morpholino; thienyl;furanyl; cyclohexyl-amino optionally substituted with an amino radical;methyl-sulfonyl; trichloromethyl; methoxy-carbonyl; chloro-methyl;butoxy-ethenyl; butoxy-ethyl; trifluoromethyl; trifluoromethoxy;ethoxy-carbonyl; t-butyl; amino-carbonyl; ethyl; propyl; methoxy;methoxy-methyl; carboxy; piperidinyl; piperidinyl-methyl;morpholino-methyl; diethyl-amino-methyl; isobutyl-amino-methyl;cyclopropyl-methyl-amino-methyl; isopropoxy-methyl; ethenyl;cyclopropyl; butoxy; [1,2,4]oxadiazol-5-yl optionally substituted withmethyl; piperazinyl optionally substituted with 1 to 2 radicalsindependently selected from methyl, isopropyl and methyl-sulfonyl;2-oxo-piperidin-1-yl; 2-oxo-pyrrolidin-1-yl; 2H-[1,2,4]triazol-3-yl;1-methyl-1H-[1,2,4]triazol-3-yl; pyrazolyl optionally substituted withmethyl; pyridazinyl; pyrazinyl optionally substituted with 1 to 2radicals independently selected from cyano and methyl; pyridinyloptionally substituted with 1 to 2 radicals independently selected fromhalo, methyl and amino; pyridinyl-N-oxide optionally substituted withmethyl; pyrimidinyl optionally substituted with 1 to 2 radicalsindependently selected from halo, methyl and amino; phenyl optionallysubstituted with 1 to 2 radicals independently selected from halo,methyl and trifluoromethyl; imidazolyl optionally substituted with 1 to2 radicals independently selected from methyl, ethyl and cyano-methyl;and 6-oxo-1,6-dihydro-pyridin-3-yl.
 18. The compound of claim 17 inwhich R₃ is selected from hydrogen, methyl, methyl-sulfonyl,t-butoxy-carbonyl-methyl, amino-carbonyl-methyl,methyl-[1,2,4]oxadiazolyl, cyano-methyl, carboxy, ethoxy-carbonyl,methyl-amino-carbonyl, dimethyl-amino-carbonyl, benzyl, furanyl,pyridinyl, indolyl, morpholino-carbonyl, piperidinyl-amino-carbonyl,piperidinyl-carbonyl, isopropoxy-carbonyl, amino-carbonyl,methyl-sulfanyl, methyl-amino-carbonyl, cyano, methyl-sulfonyl,methyl-piperazinyl, benzyl and phenyl optionally substituted with 1 to 2radicals independently selected from methyl, methoxy, fluoro, chloro,bromo, iodo, cyano, nitro, hydroxy-methyl, ethoxy-carbonyl,methyl-sulfonyl, dimethyl-amino, methyl-amino,cyclopropyl-aminocarbonyl, isopropoxy, trifluoromethyl andtrifluoromethoxy.
 19. The compound of claim 18 in which R₄ is methyl,hydroxy-ethyl, t-butyl, phenyl, benzyl, cyclohexyl, cyclopropyl,pyridinyl, furanyl, morpholino-carbonyl, tetrahydro-thiopyranyl,tetrahydro-thiopyranyl 1,1-dioxide and quinolinyl; wherein said phenyl,benzyl, cyclohexyl, cyclopropyl, pyridinyl, furanyl,morpholino-carbonyl, tetrahydro-thiopyranyl, tetrahydro-thiopyranyl1,1-dioxide and quinolinyl of R₄ is optionally substituted with 1 to 2radicals independently selected from methyl, cyano, carboxy,aminocarbonyl, methoxy, trifluoromethyl, isopropoxy, methyl-sulfanyl,dimethyl-amino, ethoxy-carbonyl, trifluoromethoxy,cyclopropyl-aminocarbonyl, pyridinyl-aminocarbonyl,cyclohexyl-aminocarbonyl, isoxazolyl-aminocarbonyl,dimethylamino-ethyl-aminocarbonyl, methoxy-ethyl-aminocarbonyl, nitro,amino, fluoro, chloro, bromo, hydroxymethyl,methyl-piperazinyl-carbonyl, morpholino-carbonyl andpiperidinyl-carbonyl.
 20. The compound of claim 19 in which R₆ isselected from methyl-sulfonyl-aminomethyl, bromomethyl,methyl-sulfonyl-methyl, ethyl(methyl)amino, dimethylamino, methyl,ethyl, cyano, bromo, chloro, fluoro, morpholino, methyl-piperazinyl,dimethyl-amino-ethoxy, methyl-amino-amino and hydroxyethyl(methyl)aminoand methoxy.
 21. The compound of claim 1 selected from:5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-quinolin-2-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-pyridin-2-yl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(2-hydroxy-ethyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(2,4-Dichloro-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(2,4-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-bromo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,4-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-biphenyl-4-yl-5-(4-bromo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3,4-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-1,5-diphenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-pyridin-2-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-o-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(3-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-cyclohexyl-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-tert-butyl-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(4-methoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Bromo-phenyl)-1-(3-fluoro-phenyl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-methoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(4-trifluoromethoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-tert-butyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(2-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,6-difluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2,6-dichloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(2,4,6-trifluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(2-methoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-1-phenyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-biphenyl-4-yl-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[6-(2-Fluoro-phenyl)-4-oxo-1-phenyl-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl]-benzonitrile;6-(2-Fluoro-phenyl)-5-(4-methylsulfanyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-tert-Butyl-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[6-(2-Fluoro-phenyl)-4-oxo-1-phenyl-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl]-benzoicacid methyl ester;5-(4-Butoxy-phenyl)-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Biphenyl-4-yl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-trifluoromethoxy-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Benzyl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-Cyclohexyl-6-(2-fluoro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-Chloro-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol;5,6-Bis-(4-chloro-phenyl)-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine;6-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-phenyl-3H-imidazol-4,5-b]pyridin-7-ylamine;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;5-(4-bromo-phenyl)-6-(2-fluoro-phenyl)-1-(morpholine-4-carbonyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine;2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethanol;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-thiopyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;[5,6-Bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-dimethyl-amine;5-(4-Bromo-phenyl)-1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-6-(2-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isoxazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Acetyl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzamide;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrimidin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-methyl-pyrimidin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;6-Biphenyl-4-yl-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;5-(4-chloro-phenyl)-6-(3′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-(4-imidazol-1-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-phenyl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-benzothiazol-2-yl-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-p-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-bromo-phenyl)-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;1-(4-Chloro-phenyl)-2-(4-isopropyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;5-(4-Bromo-phenyl)-1-phenyl-6-pyridin-3-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-pyridin-3-yl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2-fluoro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2′-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Fluoro-phenyl)-1-phenyl-5-(4-piperidin-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4′-trifluoromethyl-biphenyl-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-thiophen-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;{2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy]-ethyl}-dimethyl-amine;2-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-ethanol;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(3-morpholin-4-yl-propoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-(2-morpholin-4-yl-ethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-2-yl-phenyl)-1,9-dihydro-purin-6-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-piperidin-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-phenoxy-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-1-phenyl-6-(4-phenyl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-2-fluoro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-2-chloro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2-fluoro-4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(2-Chloro-4-morpholin-4-yl-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(3-Chloro-biphenyl-4-yl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-furan-3-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-Biphenyl-4-yl-5(4-chloro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[1-(3-fluoro-phenyl)-1H-pyrazol-4-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid methyl ester;5-(4-Bromo-phenyl)-6-morpholin-4-yl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(4-isopropyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazol-1-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-amino-cyclohexylamino)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-3-fluoro-phenyl)-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-benzoicacid ethyl ester;5-(4-Chloro-phenyl)-6-(2-fluoro-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3-fluoro-4-morpholin-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[3-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(3′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4′-methyl-biphenyl-4-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[2-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[2-fluoro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[2-Chloro-4-(4-methyl-piperazin-1-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[2-Chloro-4-(4-isopropyl-piperazin-1-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-o-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-m-tolyloxy-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-p-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-methanesulfonyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;7-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;9-Benzyl-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-cyclopropyl-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzonitrile;1-(4-Chloro-phenyl)-9-phenyl-2-(4-thiophen-3-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-4-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-Biphenyl-4-yl-2-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1,2-Bis-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Bromo-phenyl)-9-phenyl-2-(2-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-m-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-o-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,3-difluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-fluoro-3-methyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-nitro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-furan-3-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3,5-difluoro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-isopropoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-trifluoromethoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3,5-dimethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3,5-dimethyl-phenyl)-1,9-dihydro-purin-6-one;2-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-nitro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-furan-3-yl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3,5-difluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(2-fluoro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(5-fluoro-2-methoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-trifluoromethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-tert-butyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3-fluoro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(3′,5′-difluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(3′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4′-fluoro-biphenyl-4-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-pyridin-3-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-pyridin-3-yl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-pyridin-4-yl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-fluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-fluoro-phenyl)-1,9-dihydro-purin-6-one;2-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-indole-1-carboxylicacid tert-butyl ester;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-hydroxymethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-hydroxymethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-difluoro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-difluoro-phenyl)-1,9-dihydro-purin-6-one;7-(5-Chloro-2-methyl-phenyl)-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;9-(5-Chloro-2-methyl-phenyl)-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-dichloro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-dichloro-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2-nitro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-nitro-phenyl)-1,9-dihydro-purin-6-one;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzoicacid ethyl ester;3-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-N-cyclopropyl-benzamide;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclopropyl-benzamide;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-fluoro-2-methyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(5-fluoro-2-methyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(3-methoxy-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-methoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-methanesulfonyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-methanesulfonyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-dimethylamino-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(4-dimethylamino-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-7-(2-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(2,5-dimethyl-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-(2,5-dimethyl-phenyl)-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-7-yl]-benzoicacid ethyl ester;4-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-7-(4-methylamino-phenyl)-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(3-fluoro-4-trifluoromethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-9-(2-methoxy-5-methyl-phenyl)-2-p-tolyl-1,9-dihydro-purin-6-one;3-[1-(4-Bromo-phenyl)-6-oxo-2-p-tolyl-1,6-dihydro-purin-9-yl]-benzonitrile;3-[1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2-fluoro-4-methyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2-fluoro-4-trifluoromethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dimethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-2-fluoro-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-propyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-ethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid methyl ester;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-ethyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-isobutyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyridin-3-yl-phenyl)-1,9-dihydro-purin-6-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5,6-Bis-(4-chloro-phenyl)-1-(2-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Amino-phenyl)-5,6-bis-(4-chloro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-fluoro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-(4-methyl-piperazin-1-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(2,4-dichloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoicacid;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-hydroxymethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(morpholine-4-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(piperidine-1-carbonyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;1-(4-Chloro-phenyl)-8-(ethyl-methyl-amino)-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-8-dimethylamino-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-6-oxo-9-phenyl-2-(4-trifluoromethyl-phenyl)-6,9-dihydro-1H-purine-8-carbonitrile;8-Bromo-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(ethyl-methyl-amino)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-morpholin-4-yl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(4-methyl-piperazin-1-yl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(2-dimethylamino-ethoxy)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-(N′-methyl-hydrazino)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-8-methoxy-9-phenyl-1,9-dihydro-purin-6-one;8-Bromo-2-(4-bromo-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-2-yl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-1-phenyl-6-(4-pyridin-4-yl-piperazin-1-yl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-biphenyl-4-yl-6-(4-chloro-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-bromo-phenyl)-2-methyl-3-phenyl-5-p-tolyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-bromo-phenyl)-1-methyl-3-phenyl-5-p-tolyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-1-methanesulfonyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidine-1-carboxylicacid dimethylamide;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-2-methyl-3-phenyl-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-1-methyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-2-yl]-aceticacid tert-butyl ester;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-aceticacid tert-butyl ester;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-1-methanesulfonyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,3-d]pyrimidin-7-one;5-(4-chloro-phenyl)-6-[4-(2-methyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(4-methyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-biphenyl-4-yl-6-(4-chloro-phenyl)-3-phenyl-6H-isoxazolo[4,3-d]pyrimidin-7-one;2-[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetamide;5-(4-chloro-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-6-(4-pyridin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;[6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-7-oxo-3-phenyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-1-yl]-acetonitrile;(1-{4-[5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-1H-imidazol-4-yl)-acetonitrile;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2-ethyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2,4-dimethyl-imidazol-1-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-bromo-phenyl)-6-(4-chloro-phenyl)-1-methyl-3-phenyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-6H-isoxazolo[4,5-d]pyrimidin-7-one;6-(4-chloro-phenyl)-1-methyl-3-phenyl-5-(4-pyridin-2-yl-phenyl)-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-(4-chloro-phenyl)-2-methyl-3-phenyl-5-(4-pyridin-2-yl-phenyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one;6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(1-oxy-pyridin-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(1H-imidazol-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-6-(4-pyridin-4-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(2-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(3-methyl-1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-3-methanesulfonyl-6-[4-(1-oxy-pyridin-4-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-chloro-phenyl)-6-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(4-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(6-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid dimethylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-3-(morpholine-4-carbonyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid piperidin-1-ylamide;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-1-phenyl-3-(piperidine-1-carbonyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid isopropyl ester;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid tert-butyl ester;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid ethyl ester;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methylsulfanyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid methylamide;5-(4-Chloro-phenyl)-6-(4-isopropyl-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;5-(4-Chloro-phenyl)-6-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-3-methanesulfonyl-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Amino-pyrimidin-4-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylicacid amide;6-[4-(2-Butoxy-vinyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(2-Butoxy-ethyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(2-methyl-2H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrimidin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-[4-(6-Amino-pyrazin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;3-{4-[5-(4-Chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-pyrazine-2-carbonitrile;5-(4-Chloro-phenyl)-6-[4-(3,6-dimethyl-pyrazin-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-(4-isoxazol-4-yl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-6-[4-(1-methyl-1H-imidazol-2-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyrazin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Isopropyl-phenyl)-1-phenyl-5-m-tolyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Isopropyl-phenyl)-1-phenyl-5-(3-trifluoromethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Chloro-3-methyl-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3,5-Difluoro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3,4-Dichloro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;5-(3-Fluoro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;5-(3-Chloro-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;543-Bromo-phenyl)-6-(4-isopropyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;6-(4-Chloro-phenyl)-5-(4-isopropyl-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamide;N-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-methanesulfonamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoicacid ethyl ester;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-methanesulfonylmethyl-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclopropyl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-pyridin-3-yl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-cyclohexyl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-(2-dimethylamino-ethyl)-benzamide;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-(2-methoxy-ethyl)-benzamide;1-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;4-[1-(4-Chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid;2-(4-Bromo-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-pyrazol-1-yl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-imidazol-1-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2,9-diphenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-[1,2,4]oxadiazol-5-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-oxo-piperidin-1-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-[4-(2H-[1,2,4]triazol-3-yl)-phenyl]-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(1-methyl-1H-[1,2,4]triazol-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-hydroxy-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloromethyl-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-piperidin-1-ylmethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-morpholin-4-ylmethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-diethylaminomethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(isobutylamino-methyl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-{4-[(cyclopropylmethyl-amino)-methyl]-phenyl}-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-isopropoxymethyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-9-phenyl-2-(4-vinyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-cyclopropyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Butoxy-phenyl)-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-8-ethyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(2-chloro-pyrimidin-4-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-8-methyl-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-methyl-9-phenyl-2-(4-trifluoromethyl-phenyl)-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-cyclohexyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-(4-oxazol-5-yl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-7-phenyl-1-p-tolyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4-methoxy-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4-isopropyl-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;8-Bromo-1-(4-bromo-phenyl)-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-methoxy-9-phenyl-2-p-tolyl-1,9-dihydro-purin-6-one;1-(4-Bromo-phenyl)-6-oxo-9-phenyl-2-p-tolyl-6,9-dihydro-1H-purine-8-carbonitrile;1-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-7-phenyl-1,7-dihydro-purin-6-one;7-Benzyl-2-biphenyl-4-yl-1-(4-chloro-phenyl)-1,7-dihydro-purin-6-one;3-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;4-[2-Biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-(3-trifluoromethoxy-phenyl)-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-p-tolyl-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-(2-methoxy-5-methyl-phenyl)-1,9-dihydro-purin-6-one;2-Biphenyl-4-yl-1-(4-chloro-phenyl)-9-cyclopropyl-1,9-dihydro-purin-6-one;7-Benzyl-1-biphenyl-4-yl-2-(4-chloro-phenyl)-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(4′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(3′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(1-oxy-pyridin-4-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;2-(4-Chloro-phenyl)-1-(2′-fluoro-biphenyl-4-yl)-7-phenyl-1,7-dihydro-purin-6-one;1-(4-Bromo-phenyl)-8-ethyl-9-phenyl-2-(4-trichloromethyl-phenyl)-1,9-dihydro-purin-6-one;4-[1-(4-Bromo-phenyl)-8-ethyl-6-oxo-9-phenyl-6,9-dihydro-1H-purin-2-yl]-benzoicacid methyl ester;2-[4-(6-Amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one;1-(4-Chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one;and1-(4-Chloro-phenyl)-2-(4-methanesulfonyl-phenyl)-9-phenyl-1,9-dihydro-purin-6-one.22. A method of treating a disease mediated by the Cannabinoid-1receptor comprising administration of to a patient in need of suchtreatment of a therapeutically effective amount of a compound selectedfrom Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik:

in which: Y is selected from O, NR₇ and S; wherein R₇ is selected fromhydrogen, hydroxy and C₁₋₆ alkyl; R₁ is selected from C₅₋₁₀heteroaryl,C₃₋₁₂cyclolalkyl, phenyl and benzyl; wherein said heteroaryl,cycloalkyl, phenyl and benzyl of R₁ is optionally substituted with 1 to3 radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ and R₁₀; R₂ is selected fromC₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl and phenoxy; wherein saidheterocycloalkyl, heteroaryl, phenyl or phenoxy of R₂ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈XR₁₀ and—XR₁₀; wherein each X is independently selected from a bond,C₁₋₄alkylene and C₂₋₄alkenylene; R₃ is selected from hydrogen, halo,hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀,—XS(O)₀₋₂R₉, —XC(O)R₁₀, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈; R₄ isselected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈; R₅ is selected fromhydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene; R₆is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈; R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyland C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.
 23. The method according to claim 22 wherein the diseasemediated by the Cannabinoid-1 receptor is an eating disorder associatedwith excessive food intake.
 24. The method according to claim 23 whereinthe eating disorder associated with excessive food intake is selectedfrom obesity, bulimia nervosa, and compulsive eating disorders.
 25. Themethod according to claim 24 wherein the eating disorder associated withexcessive food intake is obesity.
 26. A method of preventing obesity ina person at risk for obesity comprising administration to said person ofabout 0.001 mg to about 100 mg per kg of a compound selected fromFormula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik:

in which: Y is selected from O, NR₇ and S; wherein R₇ is selected fromhydrogen, hydroxy and C₁₋₆alkyl; R₁ is selected from C₅₋₁₀heteroaryl,C₃₋₁₂cyclolalkyl, phenyl and benzyl; wherein said heteroaryl,cycloalkyl, phenyl and benzyl of R₁ is optionally substituted with 1 to3 radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substitutedC₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ and R₁₀; R₂ is selected fromC₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl and phenoxy; wherein saidheterocycloalkyl, heteroaryl, phenyl or phenoxy of R₂ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈XR₁₀ and—XR₁₀; wherein each X is independently selected from a bond, C₁ alkyleneand C₂₋₄alkenylene; R₃ is selected from hydrogen, halo, hydroxy, cyano,cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀,—XS(O)₀₋₂R₉, —XC(O)R₁₀, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈; R₄ isselected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈; R₅ is selected fromhydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene; R₆is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈; R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyland C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.
 27. A composition comprising a pharmaceutically acceptablecarrier and a compound selected from Formula Ia, Ib, Ic, Id, Ie, If, Ig,Ih, Ii, Ij and Ik:

in which: Y is selected from O, NR₇ and S; wherein R₇ is selected fromhydrogen, hydroxy and C₁₋₆alkyl; R₁ is selected from C₅₋₁₀heteroaryl,C₃₋₁₂cyclolalkyl, phenyl and benzyl; wherein said heteroaryl,cycloalkyl, phenyl and benzyl of R₁ is optionally substituted with 1 to3 radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substitutedC₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ and R₁₀; R₂ is selected fromC₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl and phenoxy; wherein saidheterocycloalkyl, heteroaryl, phenyl or phenoxy of R₂ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈XR₁₀ and—XR₁₀; wherein each X is independently selected from a bond, C₁ alkyleneand C₂₋₄alkenylene; R₃ is selected from hydrogen, halo, hydroxy, cyano,cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀,—XS(O)₀₋₂R₉, —XC(O)R₁₀, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈; R₄ isselected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈; R₅ is selected fromhydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene; R₆is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈; R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyland C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆ alkyl, nitro, C₁₋₆ alkyl,C₁₋₆ alkoxy, halo-substituted-C₁₋₆ alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆ alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.
 28. The use of a compound for the manufacture of a medicamentuseful for the treatment of a disease mediated by the Cannabinoid-1receptor in a human patient in need of such treatment, said compoundbeing selected from Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and

in which: Y is selected from O, NR₇ and S; wherein R₇ is selected fromhydrogen, hydroxy and C₁₋₆alkyl; R₁ is selected from C₅₋₁₀heteroaryl,C₃₋₁₂cyclolalkyl, phenyl and benzyl; wherein said heteroaryl,cycloalkyl, phenyl and benzyl of R₁ is optionally substituted with 1 to3 radicals independently selected from halo, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substitutedC₁₋₆alkoxy, —NR₈R₉, —S(O)₀₋₂R₈, —C(O)OR₈ and R₁₀; R₂ is selected fromC₃₋₈heterocycloalkyl, C₅₋₁₀heteroaryl, phenyl and phenoxy; wherein saidheterocycloalkyl, heteroaryl, phenyl or phenoxy of R₂ is optionallysubstituted with 1 to 3 radicals independently selected from halo,hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substitutedC₁₋₆alkyl, C₁₋₆alkenyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XOR₈,—XC(O)R₈, —XS(O)₀₋₂R₈, —XC(O)NR₈R₉, —XC(O)OR₈, —XOR₁₀, —XNR₈XR₁₀ and—XR₁₀; wherein each X is independently selected from a bond, C₁ alkyleneand C₂₋₄alkenylene; R₃ is selected from hydrogen, halo, hydroxy, cyano,cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy, —XNR₈R₉, —XR₁₀,—XS(O)₀₋₂R₉, —XC(O)R₁₀, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀ and —XC(O)OR₈; R₄ isselected from C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₆₋₁₀aryl-C₀₋₄alkyl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl,C₃₋₈heterocycloalkyl and C(O)R₁₁; wherein R₁₁ is selected fromC₃₋₈heterocycloalkyl and C₃₋₈heteroaryl; wherein any alkyl of R₄ canoptionally have a methylene replaced with O, S(O)₀₋₂ and NR₈; whereinany cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R₄ canoptionally be substituted with 1 to 3 radicals independently selectedfrom halo, hydroxy, cyano, nitro, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —XOR₈, —XR₁₀,—XC(O)R₁₀, —XS(O)₀₋₂R₈, —XNR₈R₉, —XC(O)NR₈R₉, —XC(O)NR₈R₁₀,—XC(O)NR₈XNR₈R₉, —XC(O)NR₈XOR₉ and —XC(O)OR₈; R₅ is selected fromhydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, —NR₈R₉,—OXOR₈, —OXR₁₀, —NR₈XOR₉, —OXNR₈R₉ and —C(O)OR₈; wherein X isindependently selected from a bond, C₁₋₄alkylene and C₂₋₄alkenylene; R₆is selected from hydrogen, halo, hydroxy, cyano, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆alkoxy,—XNR₈R₉, —XNR₈XOR₉, —XNR₈NR₈R₉, —XOXNR₈R₉, —XNR₈S(O)₂R₉, —XS(O)₂R₉, and—XC(O)OR₈; R₈ and R₉ are independently selected from hydrogen, C₁₋₆alkyland C₂₋₆alkenyl; or R₈ and R₉ together with the nitrogen atom to whichboth are attached form C₃₋₈heterocycloalkyl or C₅₋₁₀heteroaryl; and R₁₀is selected from C₅₋₁₀heteroaryl, C₃₋₈heterocycloalkyl, C₃₋₁₂cycloalkyland phenyl; wherein said heteroaryl or heterocycloalkyl of R₁₀ or thecombination of R₈ and R₉ and additionally the cycloalkyl or phenyl ofR₁₀ is optionally substituted with 1 to 3 radicals independentlyselected from halo, hydroxy, cyano, cyano-C₁₋₆alkyl, nitro, C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, phenyl,—NR₈R₈, —S(O)₀₋₂R₈ and —C(O)OR₈; wherein each R₈ is independentlyselected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.
 29. The use according to claim 28 wherein the disease mediatedby the Cannabinoid-1 receptor is selected from: metabolic disorders aswell as conditions associated with metabolic disorders includingobesity, bulimia nervosa, compulsive eating disorders, diabetes,arteriosclerosis, hypertension, polycystic ovary disease, cardiovasculardisease, osteoarthritis, dermatological disorders, hypertension, insulinresistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasisand sleep disorders, and hyperlipidemic conditions; or psychiatricdisorders such as substance abuse, psychosis, depression, anxiety,stress, epilepsy, mania and schizophrenia; or cognitive disorders suchas dementia including Alzheimer's disease, memory deficits, short termmemory loss and attention deficit disorders; or neurodegenerativedisorders such as Parkinson's Disease, cerebral apoplexy andcraniocerebral trauma, hypotension, catabolism in connection withpulmonary dysfunction and ventilator dependency; or cardiac dysfunctionincluding valvular disease, myocardial infarction, cardiac hypertrophyand congestive heart failure); or the overall pulmonary dysfunction,transplant rejection, rheumatoid arthritis, migraine, neuropathy,multiple sclerosis, Guillain-Barre syndrome, the inflammatory sequelaeof viral encephalitis, cerebral vascular accidents, inflammatory boweldisease, lupus, graft vs. host disease, T-cell mediated hypersensitivitydisease, psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barresyndrome, cancer, contact dermatitis, allergic rhinitis, ischemic orreperfusion injury, head trauma and movement disorders.
 30. The useaccording to claim 29 wherein the disease mediated by the Cannabinoid-1receptor is an eating disorder associated with excessive food intake.31. The use according to claim 30, wherein the eating disorderassociated with excessive food intake is selected from obesity, bulimianervosa, and compulsive eating disorders.
 32. The use according to claim31 wherein the eating disorder associated with excessive food intake isobesity.
 33. The use of a compound according to claim 1 for themanufacture of a medicament for the prevention of obesity in a person atrisk therefor.